A versatile ligand for palladium-catalyzed meta-c-h functionalizations

ABSTRACT

A class of mono-protected 3-amino-2-hydroxypyridine (MPAHP) ligands that enable the meta-C—H arylation of anilines, phenols, phenylacetic acids, and biologically relevant heterocyclic compounds using norbornene as a transient mediator is disclosed. The applicability of this meta-arylation methodology in the pharmaceutical industry is illustrated for heteroaryl substrates and heteroaryl iodide coupling partners, a feat made possible by using the MPAHP ligand. The enabling nature of MPAHP ligands to achieve other meta-C—H functionalization processes is also illustrated by the development of a meta-C—H amination reaction and a meta-C—H alkynylation reaction.

GOVERNMENTAL SUPPORT

This invention was made with governmental support under NIGMS 1R01GM102265 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

TECHNICAL FIELD

The present invention contemplates a method for forming acarbon-to-carbon (C—C) bond between a reactive substrate and an aromaticor heteroaromatic iodide, and the reagents that facilitate thatelectrophilic bond-formation reaction. More particularly, the new C—Cbond is formed on an aromatic or heteroaromatic substrate molecule thatwould normally direct electrophilic substitutions to ortho or parapositions instead to a position meta to a substituent already present onthe substrate through the use of a palladium catalyst, a directing groupbonded as part of the substrate, a directing ligand that is dissolved ordispersed in the reaction mixture.

BACKGROUND ART

Cyclopalladation reactions have been extensively studied since 1965.³Recently, Pd(II)-catalyzed C—H activation reactions have been shown tobe compatible with a wide range of carbon-carbon and carbon-heteroatombond-forming reactions through Pd(II)/Pd(0), Pd(II)/Pd(IV) andPd(II)/Pd(II) catalytic cycles.⁴⁻⁶ However, versatile ligands that canpromote both C—H cleavage and the subsequent functionalization stepsremain scarce and are largely limited to mono-protected amino acids(MPAAs) and pyridine/quinoline based ligands.⁷

As effective C—H functionalization often requires a synergisticrelationship between ligand and substrate coordinated to the metalcenter, it is essential to develop ligands that match with a variety ofdirecting groups so that the assembled complexes are reactive incleaving C—H bonds of a number of substrate classes.⁷ This fact isexemplified in recent efforts towards developing broadly usefulnorbornene-mediated meta-selective C—H functionalizations, wherepreviously developed ligand scaffolds have proven insufficient atpromoting reactivity with two important classes of substrates: anilinesand phenols. A general pathway for meta-arylation using norbornene as amediator is shown schematically below, where “DG” is a directing group,L_(n) is a ligand, and Ar—I is an aryl iodide coupling partner.

The norbornene insertion step from the Catellani reaction^(8,9) haspreviously been successfully combined with palladium catalyzed C—Hactivation to achieve selective C—H functionalization ofindoles.^(10,11) Recently, this key step was combined withortho-directed C—H activation to achieve a net meta-functionalizationvia a relay process.¹²⁻¹⁴ Further development of this newly emergingmeta-C—H functionalization strategy remains a significant, yet importantchallenge as it is complementary to other approaches for the directmeta-functionalization of arenes.¹⁵⁻²³

BRIEF SUMMARY OF THE INVENTION

The present invention contemplates method of forming a reaction productcontaining carbon-to-carbon (C—C) bond to an aryl or heteroarylsubstituent at a position meta to a substituent previously present onthe ring of an aromatic reactive substrate compound, and particularly asubstituted 3-amino-2-hydroxy-pyridine ligand useful in that reaction. Acontemplated method comprises the steps of heating a reaction mixture toa temperature of about 70° to about 120° C. The reaction mixturecontains i) an aromatic reactive substrate compound of Formula Idissolved or dispersed in a non-aqueous solvent having a boiling pointat 1 atmosphere of about 40° to about 200° C., that further containsdissolved or dispersed therein ii) a catalytic amount of a Pd(II)catalyst, iii) a substituted 3-amino-2-hydroxy-pyridine ligand ofFormula III is present at about 10 to about 50 mole percent based on themoles of reactive substrate, iv) an ethylenically unsaturated bicycliccompound of Formula II as a transient mediator present in excess overthe amount of reactive substrate, v) about 1.5 to about 5 equivalents ofan oxidant based on the amount of said reactive substrate, and vi) about1.1 to about 10 equivalents of a iodo-substituted aryl or heteroarylcoupling agent (Ar—I). The temperature is maintained for a time periodsufficient to carry out the C—C bond formation at a position meta to thesubstituent and form a reaction product whose structural formula isshown in Formula IA

In that reaction mixture, the iodo-substituted aryl or heteroarylcoupling agent can additionally be unsubstituted. Alternatively, theiodo-substituted aryl coupling agent can be further substituted

a) at the meta and para positions with one or two substituentsindependently selected from the group consisting of halogen (fluoro,chloro, bromo or iodo), C₁-C₇-hydrocarbyl that is straight, branched orcyclic, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—), C₁-C₇-hydrocarbylthioxy(C₁-C₇—S—), cyano, nitro, perfluoro-C₁-C₃-hydrocarbyl, carboxyC₁-C₇-hydrocarbyl, C₁-C₇-hydrocarboyl (acyl), protected hydroxyl,protected hydroxyl-substituted C₁-C₇-hydrocarbyl that is straight,branched or cyclic, di-(C₁-C₇-hydrocarbyl) C₁-C₇-hydrocarbylphosphonate,protected amino wherein the protecting group(s) contains up to 10 carbonatoms and the amine nitrogen has no reactive hydrogen, and a fused ringthat includes 3 or 4 added ring atoms, and

b) substituted at the ortho position by a carboxy C₁-C₇-hydrocarbyl orNH—C₁-C₇-hydrocarboyl group.

An iodo-substituted heteroaryl coupling agent can be further substitutedwith one or two substituents independently selected from the groupconsisting of halogen other than iodo, C₁-C₇-hydrocarbyl that isstraight, branched or cyclic, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—),C₁-C₇-hydrocarbylthioxy (C₁-C₇—S—), perfluoro-C₁-C₃-hydrocarbyl, carboxyC₁-C₇-hydrocarbyl, C₁-C₇-hydrocarboyl (acyl), a fused ring that includes3 or 4 added ring atoms and in which any nitrogen atom present is freeof reactive hydrogens.

The aromatic reactive substrate compound has a structural formula shownin Formula I, below:

wherein, Ring A is a heteroaromatic or carbocyclic aromatic ringstructure in which the bond shown to X is at the 1-position of the ringand the substituent bonded at the 1-position constitutes the substituentpreviously present on the ring. The ring position rotated clock-wisefrom the 1-position is the ortho-position at which a hydrogen (H) isbonded, and the next position clock-wise from the ortho-position atwhich another hydrogen (H) is bonded is the meta-position and is theposition at which the new C—C bond is formed.

The Ring A contains a single ring or two fused rings having a total of 5to 10 ring atoms and in which the ring bonded to X is aromatic and anyother ring fused to that aromatic ring is independently aromatic oraliphatic. A heteroaromatic ring structure that is all or a part of RingA contains one, two or three heteroatoms that can independently benitrogen, oxygen or sulfur atoms.

The Ring A optionally further contains 1, 2 or 3 substituents other thanhydrido (H) bonded to the ring atoms. Those optional substituents whenpresent are selected from the group consisting of halo other than iodo(fluoro, chloro or bromo), C₁-C₇-hydrocarbyl that is straight, branchedor includes a 4- to 6-membered ring bonded to a straight or branchedchain, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—), C₁-C₇-hydrocarbylthioxy(C₁-C₇—S—), C₁-C₂-hydrocarbyldioxy, cyano, nitro,perfluoro-C₁-C₃-hydrocarbyl, carboxy C₁-C₇-hydrocarbyl,C₁-C₇-hydrocarboyl (acyl), protected amino wherein the protectinggroup(s) contains up to 10 carbon atoms, and a fused ring.

In structural Formula I, n is zero (0) or one, such that the methylenegroup Y within the brackets is absent when n is zero, and present when nis one.

X is O (oxygen) or NPG (a nitrogen bonded to a protecting group) when nis 1, and NPG or CH₂ (methylene) when n is zero.

Ring B is a heteroaromatic single 6-membered ring or a fused 6,6- or5,6-membered ring system containing the depicted nitrogen atom and 1 or2 other nitrogen ring atoms. Z is carbon when n is zero or 1. Z isnitrogen (a) when n is zero, and (b) the double bond depicted is absentand replaced by a double bond at the position of the dashed line.

Ring B optionally further contains 1, 2 or 3 substituents other thanhydrido (H) bonded to the ring atoms. Those optional substituents whenpresent are selected from the group consisting of C₁-C₇-hydrocarbyl thatis straight, branched or includes a 4- to 6-membered ring bonded to astraight or branched chain C₁-C₃-substituent, C₁-C₇-hydrocarbyloxy,trifluoromethyl-C₁-C₃-hydrocarbyl, trifluoromethyl-C₁-C₃-hydrocarbyloxy,and a fused ring.

The reaction mixture also contains a transient mediator that is anethylenically unsaturated bicyclic compound of Formula II

wherein

A is CH₂, C═O or O,

each of R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently H,C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyloxy, C₁-C₆-hydrocarbyl carboxylate,C₁-C₆-hydrocarboyl, one or both of R⁵ plus R⁶ and R⁷ plus R⁸ togetherwith the carbon atom to which they are bonded form one or two carbonylgroups, or one each of R⁵ and R⁶, or R⁷ and R⁸ together with the atomsto which they are bonded form a further 4- to 6-membered aliphatic oraromatic ring that itself can be independently substituted with one ortwo substituent groups selected from the group consisting of aC₁-C₆-hydrocarbyl, a C₁-C₆-hydrocarbyloxy, a C₁-C₆-hydrocarbylcarboxylate and a nitro group.

The substituted 3-amino-2-hydroxypyridine ligand present in the reactionmixture has the structure of Formula III

wherein R¹⁵ is an acyl group containing 2 to about 12 carbon atoms or aperfluorinated acyl group containing 2 to about 6 carbon atoms, R¹⁶ ishydrido or C₁-C₆-hydrocarbyl, R¹⁷ is hydrido, C₁-C₆-hydrocarbyl ortrifluoromethyl, R¹⁸ is hydrido or C₁-C₆-hydrocarbyl, or R¹⁶ and R¹⁷ orR¹⁷ and R¹⁸ together with the carbon atoms to which they are bonded forma 6-membered ring with the depicted pyridine ring, m and p are the sameand are zero or 1 such that m and p are zero, the bracketed carbon atomsare absent and the NHR¹⁵ group is bonde directly to the depictedpyridine ring, and when m and p are both one, R¹⁹ and R²⁰ together withthe carbons to which they are bonded form a phenyl ring. When R¹⁶ andR¹⁷ form a 6-membered ring with the depicted pyridine ring, it ispreferred that R¹⁸ be hydrido.

In preferred embodiments, at least one of R¹⁶ and R¹⁷ is other thanhydrido. In one aspect of a preferred embodiment, R¹⁷ istrifluoromethyl. More preferably, R¹⁵ is acetyl, 1-adamantoyl ortrifluoroacetyl and R¹⁶ is hydrido. In another preferred aspect, one ofR¹⁶ and R¹⁷ is C₁-C₆-hydrocarbyl and the other is hydrido. In thisaspect, R¹⁵ is more preferably acetyl.

In some embodiments, m and p are both zero. In some preferred aspects ofthis embodiment, R¹⁶, R¹⁷, R¹⁷ and R¹⁸ are independently hydrido,C₁-C₆-hydrocarbyl or trifluoromethyl as defined above so that the ligandis a 2-hydroxypyridine derivative as is shown in Formula IIIa, below. Inother preferred

aspects of this embodiment, R¹⁶ and R¹⁷, or R¹⁷ and R¹⁸ together withtheir bonded carbons form a 6-membered aromatic ring so that the ligandis a derivative of a quinoline or isoquinoline, as are shown in FormulasIIIb and IIIc, respectively, below.

In a still further embodiment, m and p are both one and R¹⁹ and R²⁰together with the carbons to which they are bonded form a phenyl ring.In this case, the ligand is a 3-(ortho-aminophenyl)-2-hydroxypyridinederivative as is shown in Formula IIId, below.

The present invention has several benefits and advantages.

One benefit is that it provides a new route to the preparation ofmeta-substituted aromatics that are either not possible to readilysynthesize by other means or can be synthesized but require the presenceof a chemically bonded directing ligand.

An advantage of the invention is that one can prepare meta-substitutedaromatic compounds using aromatic reactive substrates whose substituentgroup(s) would usually direct a new C—C bond to an ortho position.

Another benefit of the invention is that the meta-directing ligand notbeing bonded to the aromatic substrate need not be removed by a separatereaction as compared to removal by physical separation.

Another advantage of the invention is that the desired products canoften be prepared in yields that are greater than about 50%.

Still further benefits and advantages of the invention will be apparentto the skilled worker from the discussion that follows.

Definitions

In the context of the present invention and the associated claims, thefollowing terms have the following meanings:

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The words “ortho”, “meta” and “para” are used in their usual manner todescribe benzenoid compounds that are substituted “1-2”, “1-3” and“1-4”, respectively. Those same words are also used herein as aconvenience to describe those same substitution patterns in aliphaticcompounds.

The word “hydrocarbyl” is used herein as a short hand term for anon-aromatic group that includes straight and branched chain aliphaticas well as alicyclic groups or radicals that contain only carbon andhydrogen. Thus, alkyl, alkenyl and alkynyl groups are contemplated,whereas aromatic hydrocarbons such as phenyl and naphthyl groups, whichstrictly speaking are also hydrocarbyl groups, are referred to herein asaryl groups or radicals, as discussed hereinafter.

Where a specific aliphatic hydrocarbyl substituent group is intended,that group is recited; i.e., C₁-C₄ alkyl, methyl or hexenyl. Exemplaryhydrocarbyl groups contain a chain of 1 to about 7 carbon atoms, andpreferably 1 to about 4 carbon atoms.

A particularly preferred hydrocarbyl group is an alkyl group. As aconsequence, a generalized, but more preferred substituent can berecited by replacing the descriptor “hydrocarbyl” with “alkyl” in any ofthe substituent groups enumerated herein.

Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyland the like. Examples of suitable alkenyl radicals include ethenyl(vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl,1-butenyl, 2-butenyl, 3-butenyl, decenyl and the like. Examples ofalkynyl radicals include ethynyl, 2-propynyl, 3-propynyl, decynyl,1-butynyl, 2-butynyl, 3-butynyl, and the like.

Usual chemical suffix nomenclature is followed when using the word“hydrocarbyl” except that the usual practice of removing the terminal“yl” and adding an appropriate suffix is not always followed because ofthe possible similarity of a resulting name to one or more substituents.Thus, a hydrocarbyl ether is referred to as a “hydrocarbyloxy” grouprather than a “hydrocarboxy” group as may possibly be more proper whenfollowing the usual rules of chemical nomenclature. Illustrativehydrocarbyloxy groups include methoxy, ethoxy, n-propoxy, isopropoxy,allyloxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, cyclohexenyloxygroups and the like. On the other hand, a hydrocarbyl group containing a—C(O)O— functionality is referred to as a hydrocarboyl (acyl) groupinasmuch as there is no ambiguity in using that suffix. Exemplaryhydrocarboyl and hydrocarboyloxy groups include acyl and acyloxy groups,respectively, such as acetyl and acetoxy, acryloyl and acryloyloxy.

As a skilled worker will understand, a substituent that cannot existsuch as a C₁ alkenyl group is not intended to be encompassed by the word“hydrocarbyl”, although such substituents with two or more carbon atomsare intended.

A “carboxyl” substituent is a —C(O)OH group. A C₁-C₆ hydrocarbylcarboxylate is a C₁-C₆ hydrocarbyl ester of a carboxyl group[—C(═O)—O—C₁-C₆ hydrocarbyl].

The term “aryl”, alone or in combination, means a phenyl or naphthyl orother aromatic radical. An aryl group can be carbocyclic, containingonly carbon atoms in the ring(s) or heterocyclic as a heteroaryl groupdiscussed hereinafter. A “heteroaryl” group is an aromatic heterocyclicring substituent that preferably contains one, or two, up to three orfour, atoms in the ring other than carbon. Those heteroatoms can benitrogen, sulfur or oxygen. A heteroaryl group can contain a single 5-or 6-membered ring or a fused ring system having two 6-membered rings ora 5- and a 6-membered ring. Exemplary heteroaryl groups include6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, andpyridazinyl; 5-membered ring substituents such as 1,3,5-, 1,2,4- or1,2,3-triazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl andisothiazolyl groups; 6-/5-membered fused ring substituents such asbenzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl and anthranilyl groups; and 6-/6-membered fused rings such as1,2-, 1,4-, 2,3- and 2,1-benzopyronyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl groups.

The term “halogen” means fluorine, chlorine or bromine. The termperfluorohydrocarbyl means a hydrocarbyl group wherein each hydrogen isreplaced by a fluorine atom. Examples of such perfluorohydrocarbylgroups, in addition to trifluoromethyl, which is preferred, areperfluorobutyl, perfluoroisopropyl, perfluorododecyl and perfluorodecyl.

The terms “amino-protecting group” and “amine-protecting group” as usedherein refer to one or more selectively removable substituents on theamino group commonly employed to block or protect the aminofunctionality. Examples of such amine-protecting groups include theformyl (“For”) group, the trityl group (“Trt”), the phthalimido group(“Phth”), the trichloroacetyl group, the chloroacetyl, bromoacetyl, andiodoacetyl groups. Urethane blocking groups, such as t-butoxy-carbonyl(“Boc”), 2-(4-biphenylyl)propyl-(2)oxycarbonyl (“Bpoc”),2-phenylpropyl(2)oxycarbonyl (“Poc”), 2-(4xenyl)-isopropoxycarbonyl,1,1-diphenyl-ethyl(1)oxycarbonyl, 1,1-diphenylpropyl(1)-oxycarbonyl,2-(3,5-dimethoxyphenyl) propyl(2)oxycarbonyl (“Ddz”),2-(p-5-toluyl)-propyl(2)oxycarbonyl, cyclopentanyl-oxycarbonyl,1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl,1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl,2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methyl-sulfonyl)-ethoxycarbonyl,2-(triphenylphosphino)-ethoxy-carbonyl, 9-fluoroenylmethoxycarbonyl(“Fmoc”), 2-(trimethyl-silyl)ethoxycarbonyl, allyloxycarbonyl,1-(trimethyl-silylmethyl)prop-1-enyloxycarbonyl,5-benzisoxalyl-methoxycarbonyl, 4-acetoxybenzyloxycarbonyl,2,2,2-trichloro-ethoxycarbonyl, 2-ethynyl(2) propoxy-carbonyl,cyclopropylmethoxycarbonyl, isobornyloxycarbonyl,1-piperidyloxycarbonyl, benzyloxycarbonyl (“Z”),4-phenylbenzyloxycarbonyl, 2-methylbenzyloxy-carbonyl,α-2,4,5,-tetramethylbenzyloxycarbonyl (“Tmz”),4-methoxybenzyloxycarbonyl, 4-fluorobenzyl-oxycarbonyl,4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl,2-chlorobenzyloxycarbonyl, dichlorobenzyloxycarbonyl,4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-cyanobenzyIoxycarbonyl,4-(decyloxy)benzyloxycarbonyl, and the like, the benzoylmethylsulfonylgroup, dithiasuccinoyl (“Dts”) group, the 2-(nitro)-phenylsulfenyl group(“Nps”), the 2- or 4-nitro-phenylsulfonyl (“Nos”) group,4-toluenesulfonyl (“Ts”), the diphenylphosphine oxide group, and likeamino-protecting groups.

The species of amine-protecting group employed is usually not criticalso long as the derivatized amino group is stable to the conditions ofthe subsequent reactions and can be removed at the appropriate pointwithout disrupting the remainder of the compound. A preferredamine-protecting group is a phthalimido group.

Further examples of amino-protecting groups embraced to by the aboveterm are well known in organic synthesis and the peptide art and aredescribed by, for example: T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, 2nd ed., John Wiley and Sons, New York.N.Y., Chapter 7, 1991; M. Bodanzsky, Principles of Peptide Synthesis,1st and 2nd revised ed., Springer-Verlag, New York, N.Y., 1984 and 1993;and Stewart and Young, Solid Phase Peptide Synthesis, 2nd ed., PierceChemical Co, Rockford, Ill. 1984.

The related term “protected amino” or “protected amine” defines an aminogroup substituted with an amino-protecting group discussed above.

The terms “hydroxy-protecting group” and “hydroxyl-protecting group”refer to readily cleavable groups bonded to hydroxyl groups, such as thetetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth-1-yl, methoxymethyl,methylthiomethyl, β-methoxyethoxymethyl, t-butyl, t-amyl, trityl,4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, benzyl,allyl, trimethylsilyl (“TMS”), t-butyldiphenylsilyl (“TBDPS”),(t-butyl)dimethylsilyl (“TBS” or “TBDMS”), triisopropylsilyl (“TIPS”),and 2,2,2-trichloro-ethoxycarbonyl groups, and the like. Ester groupssuch as C₁-C₆-hydrocarboyl esters such as acetate (“OAc”), propionateand hexanoate are also useful, as is a benzyl ether (“Bn”) group. Thespecies of hydroxyl-protecting groups is also usually not critical solong as the derivatized (protected) hydroxyl group is stable to theconditions of subsequent reaction(s) and the protecting group can beremoved at the appropriate point without disrupting the remainder of thecompound.

Further examples of hydroxy-protecting groups are described by C. B.Reese and E Haslam, Protective Groups in Organic Chemistry, J. G. W.McOmie Ed., Plenum Press, New York, N.Y., Chapters 3 and 4, 1973, and T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nded., John Wiley and Sons, New York, N.Y., Chapters 2 and 3, 1991.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In an attempt to expand the scope of norbornene-mediated meta-C—Harylation reactions, aniline was selected as a model substrate.Meta-functionalization of this class of substrates²⁰⁻²² is highlyvaluable as electrophilic substitution reactions predominantly affordortho- and/or para-substituted products due to the electronic directingeffects of the aniline nitrogen atom.

Because of the multiple possible reaction pathways at several steps ofthe catalytic cycle, development of a ligand to orchestrate each step isa tremendous challenge. The discovery of mono-protected3-amino-2-hydroxypyridine ligands (MPAHPs) that promote a highlyefficient meta-C—H arylation of anilines, phenols, phenylacetic acidsand heterocycles is disclosed hereinafter. This class of ligands hasalso enabled a meta-C—H amination reaction and a meta-C—H alkynylationreaction both of which, have not previously been achieved so far as isknown.

Thus, a method of forming a reaction product containing carbon-to-carbon(C—C) bond to an aryl or heteroaryl substituent at a position meta to asubstituent previously present on the ring of an aromatic reactivesubstrate compound is contemplated. Particularly contemplated inconjunction with that reaction is a substituted3-amino-2-hydroxy-pyridine ligand useful in that reaction.

A contemplated method comprises the steps of heating a reaction mixtureto a temperature of about 70° to about 120° C. The reaction mixturecontains i) an aromatic reactive substrate compound of Formula Idissolved or dispersed in a non-aqueous solvent having a boiling pointat 1 atmosphere of about 40° to about 200° C. That reaction mixturefurther contains dissolved or dispersed therein ii) a catalytic amountof a Pd(II) catalyst, iii) a substituted 3-amino-2-hydroxy-pyridineligand of Formula III is present at about 10 to about 50 mole percentbased on the moles of reactive substrate, iv) an ethylenicallyunsaturated bicyclic compound of Formula II as a transient mediatorpresent in excess over the amount of reactive substrate, v) about 1.5 toabout 5 equivalents of an oxidant based on the amount of said reactivesubstrate, and vi) about 1.1 to about 10 equivalents of aiodo-substituted aryl or heteroaryl coupling agent (Ar—I). Thetemperature is maintained for a time period sufficient to carry out theC—C bond formation at a position meta to the substituent and form areaction product whose structural formula is shown in Formula IA

In some aspects, the reaction product is recovered from the reactionmixture. Where Y is methylene, the reacted A Ring can be separated fromthe B Ring by treatment with hydrogen in the presence of a catalyst suchas palladium on charcoal, or by reaction with an acid such astrifluoroacetic acid. In other aspects, either treatment can be usedwithout isolating the product from the reaction mixture.

In that reaction mixture, the iodo-substituted aryl or heteroarylcoupling agent can no further substituent that the iodo group; i.e.,additionally be unsubstituted. Alternatively, the iodo-substituted arylcoupling agent can be further substituted a) at the meta and parapositions with one or two substituents independently selected from thegroup consisting of halogen (fluoro, chloro, bromo or iodo),C₁-C₇-hydrocarbyl that is straight, branched or cyclic,C₁-C₇-hydrocarbyloxy (C₁-C₇—O—), C₁-C₇-hydrocarbylthioxy (C₁-C₇—S—),cyano, nitro, perfluoro-C₁-C₃-hydrocarbyl, carboxy C₁-C₇-hydrocarbyl,C₁-C₇-hydrocarboyl (acyl), protected hydroxyl, protectedhydroxyl-substituted C₁-C₇-hydrocarbyl that is straight, branched orcyclic, di-(C₁-C₇-hydrocarbyl) C₁-C₇-hydrocarbylphosphonate, protectedamino wherein the protecting group(s) contains up to 10 carbon atoms andthe amine nitrogen has no reactive hydrogen, and a fused ring thatincludes 3 or 4 added ring atoms. That iodo-substituted aryl couplingagent can also be substituted b) at the ortho position by a carboxyC₁-C₇-hydrocarbyl or NH—C₁-C₇-hydrocarboyl group.

An iodo-substituted heteroaryl coupling agent can also be furthersubstituted with one or two substituents independently selected from thegroup consisting of halogen other than iodo, C₁-C₇-hydrocarbyl that isstraight, branched or cyclic, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—),C₁-C₇-hydrocarbylthioxy (C₁-C₇—S—), perfluoro-C₁-C₃-hydrocarbyl, carboxyC₁-C₇-hydrocarbyl, C₁-C₇-hydrocarboyl (acyl), a fused ring that includes3 or 4 added ring atoms and in which any nitrogen atom present is freeof reactive hydrogens.

The phrase “any nitrogen atom present is free of reactive hydrogens” andsimilar phrases are used herein to mean that a primary or secondaryamine that normally contains one or two hydrogens bonded to the aminenitrogen atom are replaced by amine protecting groups (PG) that can bethe same or different. Thus, a hydrogen that could otherwise react witha reactive group such as a isocyanate is absent. Illustrative protectinggroups for a primary amine are benzyl (Bn) and t-butoxycarbonyl (Boc),and one or the other for a secondary amine.

The aromatic reactive substrate compound has a structural formula shownin Formula I, below:

In Formula I, Ring A is a heteroaromatic or carbocyclic aromatic ringstructure in which the bond shown to X is at the 1-position of the ringand the substituent bonded at the 1-position constitutes the substituentpreviously present on the ring that was noted above. The ring positionrotated clock-wise from the 1-position is the ortho-position at which ahydrogen (H) is bonded, and the next position clock-wise from theortho-position at which another hydrogen (H) is bonded is themeta-position and is the position at which the new C—C bond is formed.

The Ring A contains a single ring or two fused rings having a total of 5to 10 ring atoms and in which the ring bonded to X is aromatic and anyother ring fused to that aromatic ring is independently aromatic oraliphatic. A heteroaromatic ring structure that is all or a part of RingA contains one, two or three heteroatoms that can independently benitrogen, oxygen or sulfur atoms.

The Ring A optionally further contains 1, 2 or 3 substituents other thanhydrido (H) bonded to the ring atoms. Those optional substituents whenpresent are selected from the group consisting of halo other than iodo(fluoro, chloro or bromo), C₁-C₇-hydrocarbyl that is straight, branchedor cyclic, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—), C₁-C₇-hydrocarbylthioxy(C₁-C₇—S—), cyano, nitro, perfluoro-C₁-C₃-hydrocarbyl, carboxyC₁-C₇-hydrocarbyl, C₁-C₇-hydrocarboyl (acyl), protected amino whereinthe protecting group(s) contains up to 10 carbon atoms, and a fusedring. Preferably, zero or 1 additional substituent is present bonded toa ring atom of Ring A.

Illustrative ring structures of Ring A include benzene and naphthalenerings, thiophene and furan rings, as well as pyridine, pyrazine,quinoline, quinoxaline, indole, indoline, indazole, dihydrobenzodioxine,and chromen-4-one rings. It is noted that in any of the Ring Aheterocyclic rings that include a nitrogen ring atom, that nitrogen atomis bonded to a C₁-C₇-hydrocarbyl group as discussed above, or to aremovable nitrogen protecting group so that no reactive hydrogen ispresent bonded to a Ring A nitrogen.

In structural Formula I, n is zero (0) or one. Thus, the methylene group(CH₂), Y, within the depicted brackets is absent when n is zero, andpresent when n is one. Z is carbon when n is zero or 1. Z is nitrogen(a) when n is zero, and (b) the double bond depicted is absent andreplaced by a double bond at the position of the dashed line. Inpreferred aspects of the invention, n is 1.

X is O (oxygen) or NPG (a nitrogen bonded to a protecting group) when nis 1, and NPG or CH₂ (methylene) when n is zero. Additionally, when n iszero, the double bond depicted is absent and is replaced by a doublebond at the position of the dashed line.

Ring B is a heteroaromatic single 5- or 6-membered ring or a fused 6,6-or 5,6-membered fused ring system containing the depicted nitrogen atomand 1 or 2 other nitrogen ring atoms. Ring B is often referred to hereinas a directing group (DG or DG′).

Preferably, when n is one, Ring B contains a single 6-membered ring andone nitrogen atom and up to three substituents other than hydrido (H)bonded to the ring atoms at ring positions other than that shown by thehydrido (hydrogen) bonded to the carbon atom adjacent to the depictedRing B nitrogen in Formula I. Those optional substituents, R¹, R² andR³, when present are selected from the group consisting ofC₁-C₇-hydrocarbyl that is straight, branched or cyclic,C₁-C₇-hydrocarbyloxy, trifluoromethyl-C₁-C₃-hydrocarbyl,trifluoromethyl-C₁-C₃-hydrocarbyloxy.

In preferred aspects of this embodiment, a Ring B is a pyridinederivative whose structural formula is shown below, where the dottedline denotes

a bond to the methylene group Y of Formula I, R¹, R² and R³ areindependently hydrido, C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyloxy ortrifluoromethyl-C₁-C₃-hydrocarbyloxy. More preferably, at least one ofR¹, R² and R³ is other than hydrido. Preferred and particularlypreferred Ring B groups are shown below with numerals identifying thecompound of Formula I in which they are exemplified.

When n is zero, exemplary Ring B ring systems include pyridine,pyrimidine, pyrazine, pyrazole, indazole and quinolone. These B ringsystems can contain one or two substituent groups such as aC₁-C₇-hydrocarbyl and a C₁-C₇-hydrocarbyloxy group.

The reaction mixture also contains a transient mediator that is anethylenically unsaturated bicyclic compound of Formula II

wherein

A is CH₂, C═O or O,

each of R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ is independently H,C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyloxy, C₁-C₆-hydrocarbyl carboxylate,C₁-C₆-hydrocarboyl, one or both of R⁵ plus R⁶ and R⁷ plus R⁸ togetherwith the carbon atom to which they are bonded form one or two carbonylgroups, or one each of R⁵ and R⁶, or R⁷ and R⁸ together with the atomsto which they are bonded form a further 4- to 6-membered aliphatic oraromatic ring that itself can be independently substituted with one ortwo substituent groups selected from the group consisting of aC₁-C₆-hydrocarbyl, a C₁-C₆-hydrocarbyloxy, a C₁-C₆-hydrocarbylcarboxylate and a nitro group.

A ethylenically unsaturated bicyclic transient mediator compound ofFormula II is present in excess over the amount of reactive substrateused. Preferably, that compound is present in an amount of about 1.2 toabout 3 equivalents relative to the reactive substrate. More preferably,that amount is about 1.5 to about 2 times the moles of reactivesubstrate. Structural formulas of illustrative transient mediatorethylenically unsaturated bicyclic compounds are shown below.

An improved transient mediator, methylbicyclo[2.2.1]hept-2-ene-2-carboxylate (NBE-CO₂Me) whose structuralformula is shown below is preferred in place of 2-norbornene that hadbeen used in prior publications.¹⁴

A ligand that can be viewed as a substituted 3-amino-2-hydroxypyridineis also present in the reaction mixture has the structure of FormulaIII, below,

wherein R¹⁵ is an acyl group containing 2 to about 12 carbon atoms or aperfluorinated acyl group containing 2 to about 6 carbon atoms, R¹⁶ ishydrido or C₁-C₆-hydrocarbyl, R¹⁷ is hydrido, C₁-C₆-hydrocarbyl ortrifluoromethyl, R¹⁸ is hydrido or C₁-C₆-hydrocarbyl, or R¹⁶ and R¹⁷ orR¹⁷ and R¹⁸ together with the carbon atoms to which they are bonded forma 6-membered ring with the depicted pyridine ring, m and p are the sameand are zero or 1. When m and p are zero, the bracketed carbon atoms areabsent and the NHR¹⁵ group is bonded directly to the depicted pyridinering. When R¹⁶ and R¹⁷ form a 6-membered ring with the depicted pyridinering, it is preferred that R¹⁸ be hydrido. When m and p are both one,R¹⁹ and R²⁹ together with the carbons to which they are bonded form aphenyl ring.

In some embodiments, when m and p are both zero, R¹⁶, R¹⁷, R¹⁷ and R¹⁸are independently hydrido, C₁-C₆-hydrocarbyl or trifluoromethyl asdefined above so that the ligand is a 2-hydroxypyridine derivative as isshown in Formula IIIa, below. Here, preferably at least one of R¹⁶,

R¹⁷ and R¹⁸ is other than hydrido. In one aspect of a preferredembodiment, R¹⁷ is trifluoromethyl. More preferably, R¹⁵ is acetyl,1-adamantoyl or trifluoroacetyl and R¹⁶ is hydrido. In another preferredaspect, one of R¹⁶ and R¹⁷ is C₁-C₆-hydrocarbyl and the other ishydrido. In this aspect, R¹⁵ is more preferably acetyl.

In other preferred aspects of this embodiment, R¹⁶ and R¹⁷, or R¹⁷ andR¹⁸ together with their bonded carbons form a 6-membered aromatic ringso that the ligand is a derivative of a quinoline or isoquinoline, asare shown in Formulas IIIb and IIIc, respectively, below.

In a still further embodiment, m and p are both one and R¹⁹ and R²⁰together with the carbons to which they are bonded form a phenyl ring.In this case, the ligand is a 3-(ortho-aminophenyl)-2-hydroxypyridinederivative as is shown in Formula IIId, below, where R¹⁶, R¹⁷ and R¹⁸are as defined above.

In preferred embodiments of a compound of Formula IIIa, at least one ofR¹⁶ and R¹⁷ is other than hydrido. In one aspect of a preferredembodiment, R¹⁷ is trifluoromethyl. More preferably, R¹⁵ is acetyl,1-adamantoyl or trifluoroacetyl and R¹⁶ is hydrido. In another preferredaspect, one of R¹⁶ and R¹⁷ is C₁-C₆-hydrocarbyl and the other ishydrido. In this aspect, R¹⁵ is more preferably acetyl. R¹⁸ ispreferably hydrido when not part of a ring system.

Structural formulas of six of these more preferred ligand compounds areshown below along with their numerical identifiers used herein.

A ligand of Formula III is present in the reactin mixture in an amountof about 10 to about 50 mole percent based on the moles of reactivesubstrate. Preferably, that amount is about 20 to about 40 mole percent.

A contemplated method utilizes an excess, about 1.5 to about 5equivalents (moles) of an oxidant per mole of reactive substrate, andpreferably about 2 to about 4 equivalents of oxidant. A silver oxidantis typically used, although oxygen and other mild oxidants can also beused. Illustrative catalysts include Ag(Piv), Ag(OAc), Ag₂O, AgTFA,AgOTf, Ag₂CO₃,

and Cu(OAc)₂. Ag(OAc) is a preferred oxidant.

A contemplated reaction is carried out with the ingredients dissolved ordispersed in a solvent and with agitation as can be provided by the useof a magnetic stir bar. Additional means of agitation such as shakingcan also be utilized.

The reaction is carried out at a temperature of about 70° to about 120°C. More preferably, the reaction temperature is about 90° to about 110°C. Because many useful solvents boil at a temperature less than 70° C.,the reactions are typically carried out in sealed containers underpressure greater than 1 atmosphere. Thus, the pressure under which theingredients are maintained is mostly that created by the solvent used atthe reaction temperature, with some contribution from the reactants.

The reaction is carried out at an above elevated temperature for a timeperiod sufficient to carry out the electrophilic insertion and form areaction product having the new carbon-carbon (C—C) bond. Reaction timesare typically about 15 to about 50 hours, with times of about 18-30hours being usual.

A contemplated solvent is a non-aqueous solvent having a boiling pointat 1 atmosphere of about 40° to about 200° C. Exemplary solvents include^(t)BuCO₂Me, hexafluoro-isopropanol (HFIP), ethyl acetate (EtOAc or EA),acetonitrile, acetone, ^(t)BuCN, ^(t)BuOMe (TBME), dioxane, toluene,t-amylOH, ^(t)Bu(C═O)Me, n-hexane, (trifluoromethyl)benzene, C₆F₆,chloroform (CClH₃), dichloromethane (DCM), and 1,2-dichloroethane (DCE).DCE, t-amylOH and HFIP are preferred among these materials.

Upon completion of the reaction, the desired product can be recovered byusual work-up procedures, or can be left in situ and reacted further asdesired. In preferred situations in which Y is methylene and Z iscarbon, the Ring B portion of the molecule is a pyridine derivative asdiscussed previously, a reaction product of Formula IA is chemicallysimilar to a benzyl ether or benzyl amine.

As such, the two portions of the reaction product can be severed at thebond between X and Y in the structural formula to provide Ring A-Prodand Ring B-Prod whose structural formulas are shown below. This cleavagecan be carried out using

chemistry utilized for benzyl protecting group cleavage as is discussedin Greene and Wuts, Protective Groups in Organic Synthesis, 3^(rd) ed.John Wiley & Sons, Inc., New York (1999). Further illustrative cleavagereactions are illustrated hereinafter.

Results and Discussion

The initial evaluation of aniline substrates focused on finding areactive and readily removable directing group that would be compatiblewith the desired catalytic cycle. The screening reaction used toidentify a useful directing group (DG) is illustrated below in Table 1along with eight aniline derivatives examined.

After a survey of the several directing groups, a benzylic-pyridinebased directing group bonded to the aniline amine nitrogen along with at-Boc protecting group (PG) was found to provide the meta-arylatedproduct in 13% yield. Other directing groups were not reactive, as isshown.

TABLE 1

  NR

  NR

  NR

  NR

  NR

  NR

  NR

  13%, 75% SM

NR = no reaction; SM = starting material; The yield was determined by ¹HNMR.

Ligands that could match with this directing group and promote thereaction were sought, starting with both amino acid- and heterocyclicbase-derived ligands that have been shown to promote C—H activationreactions^(7,12). Unexpectedly, there was no significant improvement ofthe yield when utilizing either of these previously established ligandclasses. These results are surprising given the enabling role of thepyridine-derived ligand L1 in the norbornene-mediated meta-C—H arylationof phenylacetic acid derived substrates previously reported by theinventor and co-workers.¹² Phosphine (L4 and L5) and N-heterocycliccarbene (L6) ligands were also evaluated, but neither class provided asignificant improvement of the yield. This indicated that design of anew ligand would be crucial for developing broadly useful meta-C—Hfunctionalizations of anilines utilizing this approach. See Table 2below for results with ligands L1-L11.

TABLE 2*

PPh₃ L4 9%, 87% SM

No Ligand 13%, 79% SM *The yields were determined by ¹H NMR; SM =starting material.

Considering that the MPAAs have been shown to be highly versatileligands that promote palladium(II) catalyzed C—H functionalizationreactions of C(sp²)-H and in some cases C(sp³)-H bonds,^(24,25) thevital structural features of this ligand were sought to be incorporatedinto other backbones that would enable new reactivity. Although varyingthe side chain of MPAA ligands permits tuning of their stericproperties, modulation of the electronic properties of the C- andN-termini (COOH and NHPG, respectively, PG=protecting group such as Ac,Boc) remains limited. Notably, both computational studies andexperimental investigations indicated the NHAc and COOH moieties areessential for forming a bis-dentate complex with Pd(II), generating theactive catalytic species.^(26,27)

Computational work has also identified a transition state in which thePd—NAc or Pd-NBoc moiety can assist C—H deprotonation in the C—Hcleavage step.^(26,27) Recognizing the similarity of 2-hydroxypyridineand 2-pyridone tautomers with the various coordination modes of acarboxylate in MPAA ligands (below), MPAHP ligands were designed andprepared based on a hydroxypyridine scaffold that also incorporates theNHAc group from the MPAAs. A schematic that illustrates these ligandsand their structural differences is shown below, where PG is aprotecting group.

It is important to emphasize that MPAHP ligands were not only designedto act as structural mimics of the MPAAs but also to address the limitedopportunities for electronic tuning of the latter ligand class.Specifically, as indicated above, substitution of the aromatic ring ofMPAHP ligands permits significant modulation of electronic propertiesand hence, binding of the OH and NHAc groups (owing to their conjugationto the aromatic ring) to the Pd(II) catalyst. Illustrative ligandsexamined are shown in Table 3 below along with yield data for the use ofeach in the model ligand screening reaction shown in the previous table.

With these newly prepared ligands in hand, their use in a model systemwas investigated, and it was found that the yield approximately tripledwith the introduction of L12.

TABLE 3*

*The yields were determined by ¹H NMR; SM = starting material.

The use of a MPAHP ligand permits the use of a wide range of couplingpartners such as a heteroaryl iodide, an alkynyl bromide and an N—OBzamine as are exemplarily illustrated below.

Coupling Partners Enabled by Use of a MPAHP Ligand

Similarly, use of a MPAHP ligand permits the use a wide range ofsubstrates as are exemplarily shown below.

Given the importance of synergy between directing group and ligand forefficient C—H functionalization, the directing groups were re-examined.The effects of several directing groups were examined under standardizedconditions as is shown in Table A, below. As shown by the data, it was

TABLE A

The yield was determined by ¹H NMR; SM = starting material; The yieldsin parentheses are isolated yields.found that electron rich benzylic pyridine-based directing groupsmatched well with this ligand scaffold, with a commercially availabledirecting group (DG, shown below) cooperating with the ligand

to provide the desired product in 98% isolated yield. With the optimizedreaction conditions in hand, the scope of substrate reaction wasexamined.

As can be seen in Tables 4-7 below, the substrate scope of thistransformation is very broad. Electron-donating and electron-withdrawinggroups (5a-o) are well tolerated at both the ortho- and meta-positionsof the aniline. It is noteworthy that the commonly troublesome cyano andnitro functionalities (5j, 5k) are well tolerated in this reaction whenutilizing an improved transient mediator, methylbicyclo[2.2.1]hept-2-ene-2-carboxylate (NBE-CO₂Me), in place of2-norbornene.¹⁴

Interestingly, unsubstituted aniline 1j and para-substituted substrate1p showed high selectivity for the di-substituted product, whereas4-methoxy substituted aniline 1q showed high mono-selectivity. It ishypothesized that after the initial arylation of substrate 1q, aconformational change is induced wherein the methyl group on the methoxyis primarily positioned away from the newly installed aryl ring,blocking the alternative meta-position which prevents di-arylation.

TABLE 4*

*In the above and following three tables: DG = directing group; Ar—I =methyl 2-iodobenzoate; Ar = 2-(carboxymethyl)phenyl; NBE—CO₂Me = methylbicyclo[2.2.1]hept-2-ene-2-carboxylate; Boc = tert-butyloxycarbonyl; Ac= acetyl; Bn = benzyl. The values under each structure indicate isolatedyields. Substrates 1a-w and 2a-l were arylated using L12 in1,2-dichloroethane. For substrates 1g, 1j, 1k, 2a, 2d and phenolsubstrates 3a-l, NBE—CO₂Me was used; other substrates were arylatedusing 2-norbornene as mediator. The selectivity of the mono- anddi-arylated products was determined by ¹H NMR analysis using CH₂Br₂ asan internal standard.

A deeper investigation into the scope of this reaction revealed thatheterocyclic substrates (2a-l), which are commonly incompatible with C—Hcross-coupling methodology, were well tolerated in this reactionproviding good to excellent yields of products 6a-l, as shown in Table 5below. Importantly, the yield of product 6b was reduced to 4% in theabsence of L12, thus indicating the importance of the ligand to achievea broad substrate scope for this transformation.

TABLE 5*

*Het = heteroaromatic.

Being interested in further examining the breadth of this reaction, wasnext evaluated meta-C—H arylation of phenol^(28,29)-derived substratesbearing benzylic pyridine based directing groups was next evaluated.³⁰Although good yields were obtained with the same directing group thatwas utilized for the aniline derived substrates, deprotection provedproblematic. To circumvent this problem, a 2,3-lutidine deriveddirecting group (DG′, whose structure is shown adjacent to the reactionscheme in Table 6) was used that is removed by hydrogenolysis withcatalytic palladium on carbon under 30 bar hydrogen.

As shown in Table 6, a variety of phenols could be successfully arylatedat the meta-position utilizing methylbicyclo[2.2.1]hept-2-ene-2-carboxylate (NBE-CO₂Me) and a modified ligand(L14). Successful use of both ligand attests to the importance of beingable to tune the electronics of this newly disclosed ligand scaffold.

Intriguingly, although substrate 1j shows high selectivity fordi-arylated product, phenolic substrate 3d provides a mono:di ratio of1:1. This result is attributed to the phenolic substrates being slightlyless reactive than their aniline counterparts.

TABLE 6*

*Substrates 3a-l and 4a-l were arylated using L14 in chloroform;substrate 3h was arylated using L12 in chloroform for 36 hours.

To more fully explore the scope of this methodology, the activity ofthis ligand was examined with substrates containing native heterocyclesas directing groups. Gratifyingly, heterocyclic substrates that form6-membered palladacycles upon cyclopalladation worked exceedingly well.Substrates directed by native pyridine, pyrimidine, pyrazine, pyrazole,indazole, isoindazole and isoquinoline were all successfully arylated atthe previously inaccessible meta-positions as is seen in Table 7, below.

As all of these substrates are unsubstituted, the mono:di ratio appearsto be loosely correlated to the coordination strength of the variousheterocyclic directing groups with weaker coordinating directing groupstending away from highly di-selective arylations. Dotted bond lines inthat table indicate the presence of diarylation products with the ratioof mono:di products being shown. Importantly, the ligand should bepresent for this reaction to proceed in synthetically useful yields withall of the substrate classes shown in Table 7.

TABLE 7*

*Het = heteroaromatic.

The effects of solvent and oxidation on the arylation in the standardreaction were also examined. Those results are illustrated by thereaction scheme and results shown below in Tables 8a and 8b.

TABLE 8a

Entry Solvent BP (° C.) 2 (%) 1 (%) 1 PhCH₃ 110 24 65 2 PhCF₃ 101 31 643 TBME 131 20 78 4 Dioxane 101 37 51 5 EA 77 30 67 6 CH₃CN 82 36 47 7t-Amyl-OH 102 35 53 8 DCM 40 34 64 9 DCE 84 42 58 10 CHCl₃ 61 42 57 11Acetone 56 38 60 12 DMF 153 14 85 The yields were determined by ¹H NMR.

Thus, use of each of the above-listed solvents provided product.However, DCE and chloroform (CHCl₃) provided the highest yield ofproduct (2) and the lowest amount of residual starting material (1).

TABLE 8b

Entry Oxidant 2 (%) 1 (%) 1 — 2 84 2 AgOAc 42 58 3 Ag₂CO₃ 12 82 4 Ag₂O 690 5 AgF <1 <1 6 AgNO₃ 4 88 7 AgOBz 17 76 8 AgOPiv 10 87 9 AgOTs <1 <110 K₂S₂O₈ <1 <1 11 Na₂S₂O₈ <1 <1 12 BQ <1 44 13 Phl(OAc)₂ 2 64 14Cu(OAc)₂ <1 <1 The yields were determined by ¹H NMR.

As is seen from the data above, silver acetate (AgAOc) provided the bestyields of the several oxidants examined.

Several removable aniline-nitrogen protecting groups (PG) were studiedfor their effect if any on product yield. As is seen from the data inTable 8c, below, most were useful, with t-boc providing the greatestyield in the conditions examined. The protecting groups (PG) used are

TABLE 8c*

*The yields were determined by ¹H NMR; SM = starting material. Ac =acetyl, Piv = pivaloyl, Boc = t-butoxycarbonyl, Cbz = benzyloxycarbonyl,Troc = 2,2,2-trichloro-ethoxycarbonyl, Fmoc =9-fluorenylmethoxycarbonyl, Ms = methanedulfonyl, Tf =trifluoromethanesulfonyl, and Nos = nitrobenzenesulfonyl.

Having thoroughly examined the substrate scope of this reaction, focuswas turned to evaluating the coupling partner scope using aniline 1a asthe model substrate. Although 3-aryl-5-methyl anilines are alternativelyaccessible via Suzuki-coupling of the commercially available3-bromo-5-methylaniline, Compound 1a was chosen as the model substrateto investigate the reactivity of a wide range of aryl iodides as it isrelatively electron neutral when compared to alternatively substitutedanilines.

Experimental results shown in Table 9, below, indicate that thisreaction exhibited an exceptionally broad coupling partner scope whenutilizing a modified norbornene.¹⁴ Electron donating and electronwithdrawing groups at the para- and meta-positions of the aryl iodidecoupling partner were well tolerated, providing the desired products ingood yields (9a-y).

TABLE 9*

R = H 9a, 87% Ph 9b, 79% Me 9c, 82% CH₂OTBS 9d, 83% OMe 9e, 81% OTBS 9f,65% CH₂PO(OEt)₂ 9g, 92% R = SMe 9h, 70% NBnBoc 9i, 80% F 9j, 92% Cl 9k,83% Br 9l, 82% I 9m, 67% CO₂Me 9n, 92% R = COMe 9o, 87% CHO 9p, 96% CF₃9q, 97% NO₂ 9r, 88% CN 9s, 89%

R = CO₂Me 9t, 88% F 9u, 86% I 9v, 74% Me 9w, 82% OMe 9x, 85%

*In Tables 9-11: TBS = tert-butyldimethylsilyl; Ts = 4-toluenesulfonyl;NBE-CO₂Me = methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate. The valuesunder each structure indicate isolated yields. Reaction conditions:Substrate (0.1 mmol), Ar—I (0.2 mmol), Pd(OAc)₂ (10 mol %), L12 (20 mol%), NBE-CO₂Me (1.5 equiv.), AgOAc (3.0 equiv.), 1,2-dichloroethane (0.5mL), 100° C., 24 hours.

Interestingly, this reaction was not limited to simple aryl iodides andan array of heterocyclic aryl iodides worked well in this reaction(9ae-ba). Indoles, thiophenes, furan, indazole, quinoline, quinazoline,and a range of pyridines were suitable coupling partners, showcasing theutility of this reaction for medicinal chemistry efforts whereheterocyclic motifs are prevalent. These results are shown in Table 10,below.

TABLE 10

*For 9ap, 9av, 9ba, 9bb and 9bc, Pd(OAc)₂ (20 ml %) and L12 (40 mol %)were used.

To determine whether the broad coupling partner scope observed in thisreaction was enabled by the ligand, the reaction was carried out underthe optimized conditions with 2-chloro-4-iodopyridine in the absence ofL12 and found the yield to be 9% by ¹H NMR. This result highlights theimportance of the MPAHP ligands for this transformation.

In order to fully investigate the compatibility of this reaction withheterocycles, the efficiency of coupling heterocyclic substrates withheterocyclic aryl iodides was examined. As can be seen in Table 11,(compounds 9bb-9bh), this ligand enables the coupling of heterocycliccoupling partners with heterocyclic substrates in good to excellentyields. Furthermore, the scalability of this reaction was demonstratedby performing the meta-C—H coupling of aniline substrate 1a ongram-scale with 5 mol % Pd(OAc)₂ and 5 mol % L12, providing the desiredproduct cleanly in 93% yield.

TABLE 11*

Given the efficiency of the meta-C—H coupling of aniline substrates on apreparative scale, the applicability of this methodology was sought tobe demonstrated using medicinally relevant compounds. Recently, the drugthalidomide and its derivatives pomalidomide and lenalidomide (IMiDs)have been repurposed for several clinical indications including multiplemyeloma (MM) and myelodysplasia. Crystallographic evidence for IMiDbinding to a key target, cereblon (CREN),³¹ suggests that chemicalmodification of the solvent-exposed phthalimide part of the IMiDs couldlead to molecules with altered specificity.

Efforts were therefore initiated to evaluate the feasibility of applyingthe ligand enabled, meta-C—H arylation of aniline derivatives tofunctionalize the solvent-exposed, meta-position of lenalidomide. Thisexemplifies a scenario where utilizing norbornene-mediated meta-C—Hfunctionalization is advantageous as it allows elaboration of the parentdrug molecule in relatively few steps. Gratifyingly, the meta-arylationof a lenalidomide derivative proceeded smoothly to provide the desiredproduct (Compound 11) in 61% isolated yield (below). The successfulutilization of the

norbornene mediated meta-C—H functionalization in this setting showcasesthe potential utility of this reaction in drug discovery.

Recognizing the robust nature of the MPAHP ligands, an improvement ofthe practicality of the reaction conditions in collaboration withBristol-Myers Squibb. A high throughput screen was undertaken toestablish Ag-free conditions with process friendly solvents. Throughthis screen, it was found that the use of CsOAc in place of AgOAc int-Amyl-OH could provide excellent yields on gram-scale reactions withortho-substituted aryl iodides, and synthetically useful yields withsimple aryl iodides when utilizing L12 or L17 respectively as areillustrated in the reaction schemes below. The

removal of silver from the Pd(II) catalyzed, norbornene mediatedmeta-C—H arylation reaction for the first time is crucial for adoptingthis method in synthesis, especially when reactions need to be performedbeyond gram-scale.

The applicability of this ligand scaffold in promoting othertransformations was attempted in other challenging meta-C—H aminationreactions. After systematic optimization, the MPAHP ligand L24 was foundto promote the norbornene mediated meta-amination of a variety ofanilines with N—O benzoyl morpholine to provide Compounds 10a-j insynthetically useful yields. These reactions are illustrated below inTable 12.

TABLE 12*

*Bz = benzoyl; DCM = dichloromethane; Boc = tert-butyloxycarbonyl; Bn =benzyl; NBE-CO₂Me = methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate.Reaction conditions: Compound 1 or 2 (0.1 mmol), aminating reagent (0.15mmol), Pd(OAc)₂ (10 mol %), L24 (10 mol %), NBE-CO₂Me (1.5 equiv.),AgOAc (2.0 equiv.), dichloromethane (1.0 mL), 100° C., 24 hours. ForCompounds 10f, 10n and 10o, Pd(OAc)₂ (15 mol %), L24 (15 mol %), AgOAc(3.0 equiv.) and NBE-CO₂Me (3.0 equiv.) were used.

Although linear amines do not work well in this transformation under thecurrent conditions, a variety of 6-membered amines can be smoothlycoupled to provide 10k-o. These results are also shown in Table 12,above. This is believed to be the first report of a meta-C—H aminationreaction in the literature.³²

Furthermore, due to the robust catalysis enabled by the MPAHP ligands,the possibility of utilizing alkynyl bromides as coupling partners toprovide meta-alkynylated products was considered. It is important tonote that this reaction has no precedent in the Catellani reaction, andit is believed that no meta-C—H alkynylation reactions have beenreported. To our great delight, after a brief evaluation of MPAHPligands and reaction conditions, meta-C—H alkynylation of a variety ofaniline-derived substrates could be achieved, providing Compounds 14a-jin good yields. This reaction scheme and results are shown in Table 13,below.

TABLE 13*

*TIPS = triisopropylsilyl; TBS = tert-butyldimethylsilyl Reactionconditions: Compounds 1 or 2 (0.1 mmol), alkynylating reagent (0.2mmol), Pd(OAc)₂ (10 mol %), L25 (30 mol %), NBE-CO₂Me (2.5 equiv.),Ag₂CO₃ (1.5 equiv.), LIF (2.0 equiv.), dichloromethane (1.0 mL), 100°C., 24 hours.

Given that the original report^(12,14) of this norbornene-mediatedmeta-C—H arylation strategy required installation of a directing groupwith phenylacetic acid substrates, wheteher the MPAHP ligands couldenable a meta-C—H arylation of phenylacetic acids using the free acid asthe directing group was examined. Indeed, as can be seen from thereaction scheme and results shown in the reaction scheme shown below,2-methylphenylacetic acid could be arylated at the meta-position in thepresence of MPAHP L24 to provide Compound 15 in 85% isolated yield.Importantly, all three of the palladium-catalyzed transformations shownin the reaction schemes of Tables 12 and 13, and that below that wascarried out in hexafluoroisopropanol (HFIP) are ligand-enabled andprovide only trace product amounts in the absence of an MPAHP ligand.

A versatile ligand scaffold for Pd(II) catalyzed meta-C—H arylation of awide range of arenes using norbornene as a transient mediator isdisclosed. Heterocyclic substrates and coupling partners are welltolerated under the developed reaction conditions, which should enablerapid uptake of this ligand enabled methodology in drug discovery. Theutility of this ligand is further demonstrated by enabling thedevelopment of both a challenging meta-C—H amination reaction and anunprecedented meta-C—H alkynylation reaction. In addition, in the caseof phenylacetic acid substrates, installation of a directing group isomitted as the MPAHP ligand promotes the meta-C—H functionalization ofthis class of substrates using the native acid as the directing group.

Methods Summary

General Procedure for the MPAHP-Promoted Norbornene-Mediated Meta-C—HActivation of Anilines.

Substrate (0.1 mmol), Ar—I (0.2 mmol), Pd(OAc)₂ (2.2 mg, 10 mol %), L12(3.0 mg, 20 mol %), AgOAc (50.1 mg, 0.3 mmol), 2-norbornene (14.1 mg,0.15 mmol) or NBE-CO₂Me (21.6 mg, 0.15 mmol) and 1,2-dichloroethane (0.5mL) were added to a 2-dram vial. The vial was capped and closed tightly,then the reaction mixture was stirred at 100° C. for 24 hours. Aftercooling to room temperature, the mixture was passed through a pad ofCelite® with dichloromethane as the eluent to remove the insolubleprecipitate. The resulting solution was concentrated and purified bypreparative TLC to afford the desired arylated product.

General Information

2-Norbornene and AgOAc were purchased from Sigma-Aldrich. NBE-CO₂Me(methyl bicyclo[2.2.1]hept-2-ene-2-carboxylate) was synthesizedfollowing literature procedures. [Shen et al., J. Am. Chem. Soc.137:11574-11577 (2015).] Solvents were obtained from Sigma-Aldrich,Alfa-Aesar and Acros and used directly without further purification.Analytical thin layer chromatography was performed on 0.25 mm silica gel60-F254. Visualization was carried out with UV light and Vogel'spermanganate. ¹H NMR was recorded on Bruker AMX-400 instrument (400 MHz)or Bruker DRX-600 instrument (600 MHz). Chemical shifts were quoted inparts per million (ppm) referenced to 0.0 ppm for tetramethylsilane. Thefollowing abbreviations (or combinations thereof) were used to explainmultiplicities: s=singlet, d=doublet, t=triplet, q=quartet, p=pentet,sext=sextet, sep=septet m=multiplet, br=broad. Coupling constants, J,were reported in Hertz unit (Hz). ¹³C NMR spectra were recorded onBruker AMX-400 instrument (100 MHz) or Bruker DRX-600 instrument (150MHz), and were fully decoupled by broad band proton decoupling. ¹⁹F NMRspectra were recorded on Bruker AMX-400 instrument (376 MHz), and werefully decoupled by broad band proton decoupling. Chemical shifts werereported in ppm referenced to either the center line of a triplet at77.0 ppm of chloroform-d or referenced to the center line of a septet at39.52 ppm of DMSO-d₆. High-resolution mass spectra (HRMS) were recordedon an Agilent Mass spectrometer using ESI-TOF (electrosprayionization-time of flight).

Preparation of Aniline Substrates

Boc-protected anilines (S1) were synthesized following literatureprocedures starting from the free anilines. Substrates 1a-w weresynthesized following the general procedure.

General Procedure for Synthesis of Boc-Protected Amines S1:

To a solution of anilines in ethanol was added (Boc)₂O (1.1 equiv.) atroom temperature. After the reaction was completed, the solution wasconcentrated under vacuum to afford the Boc-protected amines in highyield. The Boc-protected amines were used for next step without furtherpurification. [Vilaivan, Tetrahedron Lett 47, 6739-6742 (2006).]

General Procedure for Synthesis of Substrates 1a-w:

To a solution of Boc-protected anilines S1 (1.2 equiv.) in DMF was addedNaH (3.0 equiv.) at 0° C., and the resulting mixture was allowed to warmup to room temperature for 30 min. The mixture was cooled to 0° C.again, then 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride(1.0 equiv.) was added into the mixture slowly. The resulting mixturewas allowed to warm up to room temperature for another 12 hours. Afterthe reaction completed, EtOAc was added to dilute the reaction mixture,then the organic phase was washed with water, brine and dried overNa₂SO₄. After concentrated by rotatory evaporation, the residue waspurified by silica gel chromatography to afford the desired substrates1a-w.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(m-tolyl)carbamate (1a)

Colorless solid, mp=73° C., ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.10(t, J=7.7 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 6.91 (d, J=7.5Hz, 1H), 4.90 (s, 2H), 3.72 (s, 3H), 2.27 (s, 3H), 2.21 (s, 6H), 1.39(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.62, 155.18, 154.78, 148.91,142.70, 138.03, 128.05, 126.95, 126.29, 124.57, 123.68, 123.50, 80.14,59.83, 53.54, 28.25, 21.34, 13.19, 10.40; HRMS (ESI-TOF) m/z Calcd forC₂₁H₂₉N₂O₃ [M+H]⁺: 357.2173, found: 357.2172.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(3-methoxyphenyl)carbamate(1b)

Colorless solid, mp=65° C., ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.13(t, J=8.2 Hz, 1H), 6.84 (d, J=7.4 Hz, 2H), 6.70-6.63 (m, 1H), 4.90 (s,2H), 3.73 (s, 3H), 3.72 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.40 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.62, 159.49, 155.04, 154.68, 148.97,144.04, 128.84, 124.62, 123.67, 118.87, 112.47, 111.17, 80.29, 59.84,55.23, 53.51, 28.27, 13.20, 10.39; HRMS (ESI-TOF) m/z Calcd forC₂₁H₂₉N₂O₄ [M+H]⁺: 373.2122, found: 373.2121.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(3-(methylthio)phenyl)carbamate(1c)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.18-7.11 (m,2H), 7.07-6.97 (m, 2H), 4.89 (s, 2H), 3.72 (s, 3H), 2.40 (s, 3H), 2.21(s, 3H), 2.20 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.62,154.88, 154.56, 148.92, 143.30, 138.20, 128.52, 124.82, 124.65, 123.89,123.65, 123.30, 80.37, 59.81, 53.31, 28.21, 15.89, 13.16, 10.36; HRMS(ESI-TOF) m/z Calcd for C₂₁H₂₉N₂O₃S [M+H]⁺: 389.1893, found: 389.1893.

tert-Butyl(3-(benzyl(tert-butoxycarbonyl)-amino)phenyl)-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1d)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.31-7.02 (m,8H), 6.88 (d, J=7.4 Hz, 1H), 4.84 (s, 2H), 4.73 (s, 2H), 3.71 (s, 3H),2.19 (s, 3H), 2.16 (s, 3H), 1.44-1.30 (m, 18H); ¹³C NMR (150 MHz, CDCl₃)δ 163.55, 154.78, 154.50, 154.46, 148.85, 143.15, 142.72, 138.49,128.17, 128.02, 127.20, 126.84, 124.51, 124.17, 123.87, 123.73, 123.50,80.29, 80.19, 59.73, 53.82, 53.27, 28.13, 28.11, 13.09, 10.25; HRMS(ESI-TOF) m/z Calcd for C₃₂H₄₂N₃O₅ [M+H]⁺: 548.3119, found: 548.3120.

tert-Butyl (3-fluorophenyl) ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate (1e)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.18 (q, J=7.4Hz, 1H), 7.10-6.97 (m, 2H), 6.86-6.76 (m, 1H), 4.89 (s, 2H), 3.73 (s,3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 163.68, 162.38 (d, J=245.3 Hz), 154.63, 154.37, 149.03, 144.52 (d,J=10.3 Hz), 129.15 (d, J=9.6 Hz), 124.76, 123.52, 121.78, 113.69 (d,J=23.4 Hz), 112.25 (d, J=21.0 Hz), 80.68, 59.86, 53.27, 28.17, 13.20,10.33; ¹⁹F NMR (376 MHz, CDCl₃) δ −113.42; HRMS (ESI-TOF) m/z Calcd forC₂₀H₂₆FN₂O₃ [M+H]⁺: 361.1922, found: 361.1920.

tert-Butyl(3-chlorophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1f)

Colorless solid, mp=68° C., ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.29(s, 1H), 7.21-7.12 (m, 2H), 7.12-7.04 (m, 1H), 4.88 (s, 2H), 3.73 (s,3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 163.68, 154.60, 154.35, 149.06, 144.17, 133.61, 129.15, 126.59,125.52, 124.78, 124.51, 123.52, 80.72, 59.88, 53.23, 28.19, 13.22,10.36; HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₆ClN₂O₃ [M+H]⁺: 377.1626,found: 377.1628.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(3-(trifluoromethyl)phenyl)carbamate(1g)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.54 (s, 1H),7.47 (s, 1H), 7.39-7.31 (m, 2H), 4.92 (s, 2H), 3.73 (s, 3H), 2.21 (s,6H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.75, 154.49, 154.30,149.08, 143.44, 130.58 (q, J=32.2 Hz), 129.39, 128.76, 124.89, 123.88(d, J=272.3 Hz); 123.59, 123.54, 121.95, 80.92, 59.86, 53.10, 28.16,13.20, 10.38; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.90; HRMS (ESI-TOF) m/zCalcd for C₂₁H₂₆F₃N₂O₃ [M+H]⁺: 411.1890, found: 411.1890.

Methyl3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)benzoate(1h)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.92 (s, 1H),7.78 (d, J=7.7 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.30 (t, J=7.9 Hz, 1H),4.93 (s, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H),1.40 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 166.64, 163.67, 154.63, 154.42,148.94, 142.99, 131.04, 130.33, 128.26, 127.55, 126.54, 124.72, 123.66,80.59, 59.79, 53.10, 52.01, 28.13, 13.13, 10.36; HEMS (ESI-TOF) m/zCalcd for C₂₂H₂₉N₂O₅ [M+H]⁺: 401.2071, found: 401.2072.

tert-Butyl(3-benzoylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1i)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.75 (d,J=7.4 Hz, 2H), 7.67 (s, 1H), 7.61-7.50 (m, 3H), 7.45 (t, J=7.6 Hz, 2H),7.36 (t, J=7.8 Hz, 1H), 4.93 (s, 2H), 3.72 (s, 3H), 2.26-2.16 (m, 6H),1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 196.04, 163.69, 154.63, 154.51,148.97, 142.97, 137.71, 137.35, 132.32, 130.55, 130.00, 128.21, 128.15,127.87, 127.10, 124.75, 123.63, 80.66, 59.83, 53.16, 28.18, 13.18,10.36; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₁N₂O₄ [M+H]⁺: 447.2278, found:447.2278.

tert-Butyl(3-cyanophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1j)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.66-7.54 (m,2H), 7.43-7.31 (m, 2H), 4.87 (s, 2H), 3.75 (s, 3H), 2.23 (s, 3H), 2.21(s, 3H), 1.38 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.76, 154.14,149.14, 144.04, 130.83, 129.57, 129.11, 128.74, 124.98, 123.37, 118.61,112.31, 81.20, 59.92, 52.98, 28.12, 13.23, 10.32; HRMS (ESI-TOF) m/zCalcd for C₂₁H₂₆N₃O₃ [M+H]⁺: 368.1969, found: 368.1969.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-nitrophenyl)carbamate(1k)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.18 (t, J=2.2 Hz, 1H),8.16 (s, 1H), 8.00-7.93 (m, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.41 (t, J=8.1Hz, 1H), 4.93 (s, 2H), 3.75 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.40(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.81, 154.13, 154.07, 149.15,148.12, 144.24, 132.19, 128.82, 125.02, 123.49, 121.22, 119.98, 81.36,59.92, 52.91, 28.12, 13.22, 10.36; HRMS (ESI-TOF) m/z Calcd forC₂₀H₂₆N₃O₅ [M+H]⁺: 388.1867, found: 388.1865.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)-methyl)(phenyl)carbamate (11)

Light yellow solid, mp=60° C., ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H),7.26-7.18 (m, 4H), 7.14-7.15 (m, 1H), 4.92 (s, 2H), 3.72 (s, 3H),2.25-2.17 (m, 6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.63,155.06, 154.74, 148.93, 142.74, 128.29, 126.46, 125.49, 124.63, 123.76,80.23, 59.82, 53.45, 28.23, 13.19, 10.39; HRMS (ESI-TOF) m/z Calcd forC₂₀H₂₇N₂O₃ [M+H]⁺: 343.2016, found: 343.2015.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(o-tolyl)carbamate (1m)

Light yellow liquid, rotameric mixture; ¹H NMR (400 MHz, CDCl₃) δ 8.09(s, 1H), 7.25-6.87 (m, 4H), 5.13 (d, J=14.8 Hz, 1H), 4.70-4.39 (m, 1H),3.71 (s, 3H), 2.20 (s, 6H), 2.13 (s, 3H), 1.54-1.28 (m, 9H); ¹³C NMR(150 MHz, CDCl₃) rotameric mixture, resonances for the minor rotamer areenclosed in parenthesis ( ): δ 163.68, 154.95 (155.19), 154.85 (154.37),148.85, 140.63 (141.16), 135.87 (136.15), 130.22 (130.55), 128.28,126.87, 126.06 (126.40), 124.97 (124.72), 124.87 (124.00), 79.71(80.05), 59.71, 52.50 (53.38), 28.22, 17.49 (17.63), 13.18, 10.60; HRMS(ESI-TOF) m/z Calcd for C₂₁H₂₉N₂O₃ [M+H]⁺: 357.2173, found: 357.2172.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(2-methoxyphenyl)carbamate(1n)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H), 7.12 (t, J=7.6Hz, 1H), 6.93-6.65 (m, 3H), 5.46-4.37 (m, 2H), 3.77 (brs, 3H), 3.72 (s,3H), 2.25 (s, 3H), 2.18 (brs, 3H), 1.55-1.26 (m, 9H); ¹³C NMR (150 MHz,CDCl₃) rotameric mixture, resonances for the minor rotamerthe the minorrotamer are enclosed in parenthesis ( ): δ 163.68 (163.60), 155.45(155.59), 155.32, 155.10 (154.83), 148.58, 130.61 (130.28), 129.42,127.79 (128.02), 125.35 (124.59), 124.76 (124.49), 119.95 (120.39),110.89 (111.68), 79.47 (80.09), 59.72, 55.14 (55.59), 52.42 (53.29),28.17 (28.26), 13.16, 10.57; HRMS (ESI-TOF) m/z Calcd for C₂₁H₂₉N₂O₄[M+H]⁺: 373.2122, found: 373.2121.

tert-Butyl(2-fluorophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1o)

Colorless solid, mp=59° C., rotameric mixture, ratio of therotamers=75/25; ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.40-7.06 (m,2H), 7.05-6.89 (m, 2H), 4.93 (s, 2H), 3.72 (s, 3H), 2.25 (s, 3H), 2.18(s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) rotameric mixture,resonances for the minor rotamerthe the minor rotamer are enclosed inparenthesis ( ): δ 163.79, 158.15 (d, J=248.9 Hz), 154.68, 154.30,148.72, 129.69 (d, J=12.0 Hz), 129.28, 127.90 (d, J=7.8 Hz), 125.12,124.97, 123.79, 115.56 (d, J=21.3 Hz), 80.48, 59.75, 52.69 (53.39),28.07, 13.16, 10.49; ¹⁹F NMR (376 MHz, CDCl₃) for major isomer: δ−121.13; ¹⁹F NMR (376 MHz, CDCl₃) for minor isomer: δ −120.82; HRMS(ESI-TOF) m/z Calcd for C₂₀H₂₆FN₂O₃ [M+H]⁺: 361.1922, found: 361.1922.

tert-Butyl(4-fluorophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1p)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.19 (s,2H), 6.91 (t, J=8.6 Hz, 2H), 4.88 (s, 2H), 3.72 (s, 3H), 2.21 (s, 6H),1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.72, 160.46 (d, J=244.4 Hz),154.82, 154.78, 148.96, 138.65, 128.43 (d, J=8.0 Hz), 124.81, 123.93,115.06 (d, J=22.8 Hz), 80.39, 59.85, 53.50, 28.22, 13.20, 10.40; ¹⁹F NMR(376 MHz, CDCl₃) δ −117.08; HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₆FN₂O₃[M+H]⁺: 361.1922, found: 361.1923.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(4-methoxyphenyl)carbamate(1q)

Red solid, ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.10 (brs, 2H), 6.74(d, J=8.4 Hz, 2H), 4.89 (s, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 2.25-2.16(m, 6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.67, 157.34,155.15, 155.08, 148.88, 135.52, 127.99, 124.68, 124.09, 113.56, 80.04,59.81, 55.31, 53.67, 28.28, 13.19, 10.43; HRMS (ESI-TOF) m/z Calcd forC₂₁H₂₉N₂O₄ [M+H]⁺: 373.2122, found: 373.2123.

tert-Butylbenzo[d][1,3]dioxol-5-yl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1r)

Colorless solid, mp=87° C., ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 6.77(s, 1H), 6.65 (s, 2H), 5.90 (s, 2H), 4.84 (s, 2H), 3.73 (s, 3H), 2.21(s, 3H), 2.20 (s, 3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.24,154.58, 154.53, 148.48, 146.76, 145.02, 136.32, 124.28, 123.48, 119.75,108.27, 107.11, 100.71, 79.75, 59.40, 53.38, 27.82, 12.76, 9.98; HRMS(ESI-TOF) m/z Calcd for C₂₁H₂₇N₂O₅ [M+H]⁺: 387.1914, found: 387.1914.

tert-Butyl(4-fluoro-3-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1s)

Colorless solid, mp=78° C., ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.07(s, 1H), 6.98 (s, 1H), 6.83 (t, J=9.0 Hz, 1H), 4.86 (s, 2H), 3.73 (s,3H), 2.24-2.19 (m, 6H), 2.18 (d, J=1.9 Hz, 3H), 1.39 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.68, 159.05 (d, J=243.2 Hz), 154.94, 154.81,148.90, 138.26, 129.63 (d, J=5.3 Hz), 125.69, 124.72, 124.59 (d, J=18.6Hz), 123.83, 114.59 (d, J=23.3 Hz), 80.26, 59.81, 53.58, 28.22, 14.51,13.18, 10.40; ¹⁹F NMR (376 MHz, CDCl₃) δ −121.37; HRMS (ESI-TOF) m/zCalcd for C₂₁H₂₈FN₂O₃ [M+H]⁺: 375.2078, found: 375.2079.

tert-butyl (2-fluoro-4-methoxyphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl) carbamate (1t)

Red liquid, rotameric mixture, ratio of the rotamers=75/25; ¹H NMR (400MHz, CDCl₃) δ 8.06 (brs, 1H), 7.18 (s, 0.25H), 7.00 (d, J=9.1 Hz,0.75H), 6.63-6.44 (m, 2H), 5.02-4.75 (m, 2H), 3.73 (s, 3H), 3.72 (s,3H), 2.26 (s, 3H), 2.19 (s, 3H), 1.52-1.31 (m, 9H); ¹³C NMR (150 MHz,CDCl₃) rotameric mixture: δ 163.81, 159.63, 159.41, 159.20, 159.16,159.03, 158.95, 158.01, 157.76, 154.96, 154.81, 154.66, 148.69, 130.50,129.73, 125.28, 124.99, 124.42, 122.33, 122.24, 109.53, 108.98, 101.75,101.59, 80.62, 80.22, 76.79, 59.73, 55.48, 53.61, 52.77, 28.10, 13.17,10.52; ¹³C NMR (150 MHz, CDCl₃) for major isomer: δ 163.81, 159.03,158.95, 158.58 (d, J=248.7 Hz), 154.74 (d, J=22.2 Hz), 148.69, 129.73,125.28, 124.99, 122.29 (d, J=13.1 Hz), 108.98, 101.67 (d, J=24.2 Hz),80.22, 59.73, 55.48, 52.77, 28.10, 13.17, 10.52; ¹⁹F NMR (376 MHz,CDCl₃) for major isomer: δ −119.19; ¹⁹F NMR (376 MHz, CDCl₃) for minorisomer: δ −118.92; HRMS (ESI-TOF) m/z Calcd for C₂₁H₂₈FN₂O₄ [M+H]⁺:391.2028, found: 391.2028.

Methyl3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-2-methylbenzoate(1u)

Colorless liquid, rotameric mixture, ratio of the rotamers=70/30; ¹H NMR(400 MHz, CDCl₃) δ 8.09 (brs, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.47 (s,0.3H), 7.21 (d, J=7.8 Hz, 0.7H), 7.16-7.00 (m, 1H), 5.16 (d, J=14.9 Hz,1H), 4.66-4.30 (m, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 2.50-2.30 (m, 3H),2.20 (s, 6H), 1.52-1.28 (m, 9H); ¹³C NMR (150 MHz, CDCl₃) rotamericmixture, resonances for the minor rotamerthe the minor rotamer areenclosed in parenthesis ( ): δ 168.05, 163.75 (163.65), 154.70 (154.79),154.48, 148.89, 141.94 (142.56), 137.93 (138.10), 132.50 (132.90),130.91 (131.28), 129.15, 125.50 (125.79), 124.98, 124.86 (123.85),80.07, 59.72, 52.44 (53.27), 51.85, 28.16, 15.07, 13.17, 10.61; HRMS(ESI-TOF) m/z Calcd for C₂₃H₃₁N₂O₅ [M+H]⁺: 415.2227, found: 415.2226.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)-methyl)(naphthalen-1-yl)carbamate(1v)

Colorless solid, rotameric mixture, ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s,1H), 7.87 (s, 1H), 7.84-7.77 (m, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.52-7.39(m, 2H), 7.38-7.18 (m, 2H), 5.37 (d, J=15.2 Hz, 1H), 4.66 (d, J=15.1 Hz,1H), 3.66 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 1.70-1.05 (m, 9H); ¹³CNMR (150 MHz, CDCl₃) rotameric mixture, resonances for the minor rotamerare enclosed in parenthesis ( ): δ 163.63, 155.46, 154.99, 148.89,138.66, 134.23, 130.76, 128.14, 127.27, 126.37, 125.99, 125.66, 125.32,124.75, 124.66, 122.88, 79.93, 59.69, 53.00 (53.86), 28.06, 13.13,10.54; HRMS (ESI-TOF) m/z Calcd for C₂₄H₂₉N₂O₃ [M+H]⁺: 393.2173, found:393.2173.

tert-butyl((4-methoxy-3,5-dimethylpyridin-2-yl)-methyl)(naphthalen-2-yl)carbamate(1w)

Colorless solid, mp=81° C., ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H),7.78-7.72 (m, 1H), 7.72-7.67 (m, 2H), 7.65 (s, 1H), 7.44 (d, J=8.6 Hz,1H), 7.42-7.34 (m, 2H), 5.03 (s, 2H), 3.71 (s, 3H), 2.23 (s, 3H), 2.19(s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66, 154.99,154.78, 148.97, 140.41, 133.41, 131.37, 127.73, 127.70, 127.37, 126.03,125.78, 125.36, 124.67, 123.75, 123.52, 80.43, 59.80, 53.63, 28.25,13.17, 10.43; HRMS (ESI-TOF) m/z Calcd for C₂₄H₂₉N₂O₃ [M+H]⁺: 393.2173,found: 393.2172.

tert-Butyl(3-(((tert-butyldimethylsilyl)oxy)methyl)-phenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(1x)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.23-7.15(m, 2H), 7.12 (d, J=7.9 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 4.91 (s, 2H),4.66 (s, 2H), 3.72 (s, 3H), 2.24-2.16 (m, 6H), 1.39 (s, 9H), 0.89 (s,9H), 0.04 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 163.60, 155.03, 154.79,148.95, 142.79, 141.69, 128.05, 124.93, 124.55, 123.81, 123.61, 123.03,80.17, 64.61, 64.59, 59.81, 53.46, 28.24, 25.88, 25.86, 18.32, 13.17,10.34, −5.33; HRMS (ESI-TOF) m/z Calcd for C₂₇H₄₃N₂O₄Si [M+H]⁺:487.2987, found: 487.2986.

tert-Butyl(3-benzylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1y)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.28-7.20 (m,2H), 7.20-6.99 (m, 6H), 6.91 (d, J=7.1 Hz, 1H), 4.89 (s, 2H), 3.89 (s,2H), 3.69 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.36 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.64, 155.04, 154.72, 148.88, 142.70, 141.02,140.89, 128.85, 128.35, 128.29, 127.34, 126.19, 125.94, 124.60, 123.96,123.82, 80.21, 59.79, 53.44, 41.62, 28.21, 13.20, 10.39; HRMS (ESI-TOF)m/z Calcd for C₂₇H₃₃N₂O₃ [M+H]⁺: 433.2486, found: 433.2484.

tert-Butyl[1,1′-biphenyl]-3-yl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1z)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.52-7.46(m, 2H), 7.44 (s, 1H), 7.42-7.36 (m, 2H), 7.36-7.27 (m, 3H), 7.23 (d,J=8.3 Hz, 1H), 4.97 (s, 2H), 3.71 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H),1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.68, 155.08, 154.72, 148.97,143.09, 141.32, 140.87, 128.61, 127.19, 127.07, 125.43, 125.32, 124.70,124.30, 123.82, 80.33, 59.81, 53.46, 28.28, 13.18, 10.43; HRMS (ESI-TOF)m/z Calcd for C₂₆H₃₁N₂O₃ [M+H]⁺: 419.2329, found: 419.2327.

tert-Butyl(3-bromophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(1aa)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.45 (s, 1H),7.26-7.18 (m, 2H), 7.10 (t, J=8.0 Hz, 1H), 4.87 (s, 2H), 3.74 (s, 3H),2.22 (s, 3H), 2.20 (s, 3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ163.68, 154.57, 154.33, 149.04, 149.03, 144.29, 129.46, 128.43, 125.00,124.79, 123.53, 121.55, 80.74, 59.88, 53.21, 28.18, 13.21, 10.36; HRMS(ESI-TOF) m/z Calcd for C₂₀H₂₆BrN₂O₃ [M+H]⁺: 421.1121, found: 421.1121.

Preparation of Heterocyclic-Amine Substrates

S2a and S2b were synthesized following the General Procedure A;Aminothiophenes bearing Boc-protecting group S2c-e were commercialavailable; Boc-protected amines S2f-l were synthesized following theGeneral Procedure B. Substrates 2a-l were synthesized following thegeneral procedure.

General Procedure a for Synthesis of Boc-Protected Amines S2:

To a solution of amine (5 mmol) in THF (20 mL) was added a solution ofsodium bis(trimethylsilyl)amide (2.5 N in THF) slowly at −15° C. undernitrogen, and the resulting mixture was stirred for 30 min at the sametemperature. Next, (Boc)₂O (1.1 equiv.) was added at the sametemperature. The reaction mixture was allowed to warm up to roomtemperature. After the reaction was completed, the resulting mixture wasdiluted with EtOAc (50 mL), and the organic phase was washed with water(50 mL) and then brine (50 mL), dried over MgSO₄, and concentrated invacuo. Purification of the residue by flash chromatography on silica gelgave S2. [Demont ert al., Med. Chem., 58:5649-5673 (2015).]

General Procedure B for Synthesis of Boc-Protected Amines S2:

To a solution of amine in ethanol was added (Boc)₂O (1.1 equiv.) at roomtemperature. After the reaction was completed, the solution wasconcentrated under vacuum to afford the Boc-protected amines in highyield. The Boc-protected amines were used for next step without furtherpurification. [Vilaivan, Tetrahedron Lett 47:6739-6742 (2005).]

General Procedure for Synthesis of Substrates 2a-l:

To a solution of Boc-protected amine S2 (1.2 equiv.) in DMF was addedNaH (3.0 equiv.) at 0° C., and the resulting mixture was allowed to warmup to room temperature for 30 minutes. The mixture was cooled to 0° C.again, then 2-chloromethyl-4-methoxy-3,5-dimethylpyridine hydrochloride(1.0 equiv.) was added into the mixture slowly. The resulting mixturewas allowed to warm to room temperature for another 12 hours. After thereaction completed, EtOAc was added to dilute the reaction mixture, thenthe organic phase was washed with water, brine and dried over Na₂SO₄.After concentrated in vacuo, the residue was purified by flashchromatography on silica gel to afford 2.

tert-Butyl(2-chloropyridin-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(2a)

Colorless solid, rotameric mixture, ratio of the rotamers=76/24; ¹H NMR(400 MHz, CDCl₃) δ 8.22 (d, J=4.7 Hz, 1H), 8.13 (s, 0.24H), 8.07 (s,0.76H), 7.92 (s, 0.24H), 7.66 (d, J=7.7 Hz, 0.76H), 7.22-7.10 (m, 1H),5.16 (d, J=15.4 Hz, 1H), 4.72-4.38 (m, 1H), 3.73 (s, 3H), 2.27 (s, 3H),2.20 (s, 3H), 1.50-1.29 (m, 9H); ¹³C NMR (100 MHz, CDCl₃) for majorisomer: δ 163.86, 154.04, 153.75, 150.49, 148.80, 147.43, 139.21,136.43, 125.23, 125.07, 122.51, 81.02, 59.75, 51.62, 28.03, 13.17,10.66; HRMS (ESI-TOF) m/z Calcd for C₁₉H₂₅ClN₃O₃ [M+H]⁺: 378.1579,found: 378.1579.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(6-methoxypyridin-2-yl)carbamate(2b)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.50 (t,J=7.9 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 6.37 (d, J=7.9 Hz, 1H), 5.20 (s,2H), 3.72 (s, 3H), 3.62 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.43 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.32, 162.09, 155.91, 154.45, 152.20,148.85, 139.43, 123.84, 122.42, 110.75, 104.67, 80.95, 59.82, 52.84,49.28, 28.15, 13.13, 10.32; HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₈N₃O₄[M+H]⁺: 374.2074, found: 374.2073.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(thiophen-2-yl)carbamate(2c)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 6.89 (d,J=5.5 Hz, 1H), 6.73 (dd, J=5.6, 3.8 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H),4.96 (s, 2H), 3.73 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.46 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 163.71, 154.15, 154.00, 149.00, 145.12,124.83, 124.21, 123.75, 120.38, 116.32, 81.52, 59.85, 53.87, 28.16,13.19, 10.26; HRMS (ESI-TOF) m/z Calcd for C₁₈H₂₅N₂O₃S [M+H]⁺: 349.1580,found: 349.1579.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(thiophen-3-yl)carbamate(2d)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.12-7.08(m, 1H), 7.06 (s, 1H), 6.91 (s, 1H), 4.90 (s, 2H), 3.73 (s, 3H), 2.21(s, 3H), 2.20 (s, 3H), 1.44 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.67,154.80, 154.25, 149.00, 141.18, 125.41, 124.68, 123.61, 123.18, 114.83,80.65, 59.84, 53.33, 28.23, 13.18, 10.27; HRMS (ESI-TOF) m/z Calcd forC₁₈H₂₅N₂O₃S [M+H]⁺: 349.1580, found: 349.1581.

Methyl3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)thiophene-2-carboxylate(2e)

Light yellow liquid, rotameric mixture, ratio of rotamers=34/64, ¹H NMR(400 MHz, CDCl₃) δ 8.20-7.98 (m, 1H), 7.37-7.16 (m, 1H), 6.99 (s,0.34H), 6.76 (s, 0.66H), 5.14-4.68 (m, 2H), 3.84 (s, 3H), 3.72 (s, 3H),2.25 (s, 3H), 2.20 (s, 3H), 1.50-1.28 (m, 9H); ¹³C NMR (150 MHz, CDCl₃)rotameric mixture, resonances for the minor rotamer are enclosed inparenthesis ( ): δ 163.74 (163.60), 161.44 (161.32), 154.71 (155.16),154.07 (154.16), 148.67 (148.75), 144.92 (145.84), 128.91 (129.28),128.51 (128.78), 124.97 (125.02), 124.78 (124.71), 123.92, 80.28(80.62), 59.75, 52.49 (53.43), 51.83, 28.08, 13.15, 10.50; HRMS(ESI-TOF) m/z Calcd for C₂₀H₂₇N₂O₅S [M+H]⁺: 407.1635, found: 407.1635.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(quinolin-5-yl)carbamate(2f)

Red liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.88 (dd, J=4.2, 1.6 Hz, 1H), 8.27(s, 1H), 8.09 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H),7.38 (dd, J=8.5, 4.2 Hz, 2H), 5.21 (d, J=15.3 Hz, 1H), 4.80 (d, J=15.2Hz, 1H), 3.67 (s, 3H), 2.17 (s, 6H), 1.25 (brs, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 163.73, 155.09, 154.54, 150.19, 148.97, 148.73, 138.85, 131.91,128.89, 128.74, 126.24, 125.75, 124.95, 124.53, 120.89, 80.46, 59.75,53.26, 28.07, 13.16, 10.60; HRMS (ESI-TOF) m/z Calcd for C₂₃H₂₈N₃O₃[M+H]⁺: 394.2125, found: 394.2124.

tert-Butyl(1-acetylindolin-6-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(2g)

Light yellow solid, mp=140° C., rotameric mixture, ratio ofrotamer=22/78, ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.08 (m, 1.78H), 7.15 (s,0.22H), 7.08 (d, J=7.4 Hz, 0.22H), 7.00 (d, J=8.0 Hz, 0.78H), 6.96-6.85(m, 1H), 4.95-4.84 (m, 2H), 4.09 (t, J=8.1 Hz, 0.44H), 4.02 (t, J=8.4Hz, 1.56H), 3.72 (s, 3H), 3.11 (t, J=8.5 Hz, 1.56H), 2.98 (t, J=8.5 Hz,0.44H), 2.32-2.14 (m, 9H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)rotameric mixture, resonances for the minor rotamer are enclosed inparenthesis ( ): δ 168.34 (168.19), 163.61 (163.68), 155.12 (154.97),154.79, 148.78 (148.86), 142.93 (142.18), 142.08 (141.68), 128.43(131.15), 125.15, 124.52 (124.79), 123.75 (123.89), 122.25 (121.66),115.85 (113.80), 80.16 (80.38), 59.79, 53.55 (53.60), 49.18 (48.33),28.21, 27.56 (26.39), 24.11 (24.31), 13.15, 10.44 (10.39); HRMS(ESI-TOF) m/z Calcd for C₂₄H₃₂N₃O₄ [M+H]⁺: 426.2387, found: 426.2387.

tert-Butyl6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-indole-1-carboxylate(2h)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.95 (s, 1H),7.53 (d, J=3.7 Hz, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H),6.47 (d, J=3.7 Hz, 1H), 4.99 (s, 2H), 3.72 (s, 3H), 2.23 (s, 3H), 2.19(s, 3H), 1.59 (s, 9H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.73,154.75, 154.55, 149.01, 143.94, 139.80, 139.25, 124.81, 123.72, 123.58,123.39, 120.34, 111.99, 84.65, 80.74, 59.85, 53.78, 28.20, 28.01, 13.19,10.43; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₆N₃O₅ [M+H]⁺: 482.2649, found:482.2650.

tert-Butyl4-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-indole-1-carboxylate(2i)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.97 (d, J=8.3Hz, 1H), 7.52 (d, J=3.8 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.01 (s, 1H),6.52 (d, J=3.7 Hz, 1H), 4.99 (s, 2H), 3.68 (s, 3H), 2.18 (s, 6H), 1.65(s, 9H), 1.35 (brs, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.59, 154.98,154.85, 149.65, 148.85, 135.80, 134.93, 128.51, 125.42, 124.68, 124.33,124.16, 121.07, 113.58, 105.56, 83.62, 80.08, 59.70, 53.18, 28.16,28.13, 13.14, 10.52; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₆N₃O₅ [M+H]⁺:482.2649, found: 482.2649.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(1-methyl-1H-indazol-6-yl)carbamate(2j)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.87 (s, 1H),7.55 (d, J=8.6 Hz, 1H), 7.33 (s, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.99 (s,2H), 3.98 (s, 3H), 3.73 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.40 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.70, 155.02, 154.81, 148.94, 141.45,140.01, 132.47, 124.76, 123.84, 121.90, 120.82, 120.45, 106.53, 80.50,59.84, 53.92, 35.50, 28.25, 13.21, 10.46; HRMS (ESI-TOF) m/z Calcd forO₂₂H₂₉N₄O₃ [M+H]⁺: 397.2234, found: 397.2234.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(4-oxo-2-phenyl-4H-chromen-6-yl)carbamate(2k)

Yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.99 (d, J=2.6 Hz,1H), 7.94-7.87 (m, 2H), 7.78 (d, J=9.1 Hz, 1H), 7.57-7.49 (m, 3H), 7.47(d, J=9.0 Hz, 1H), 6.77 (s, 1H), 4.98 (s, 2H), 3.74 (s, 3H), 2.24 (s,3H), 2.20 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 177.99,163.75, 163.22, 154.50, 153.76, 149.03, 140.32, 133.36, 131.73, 131.53,128.99, 126.22, 124.84, 123.84, 123.68, 121.85, 117.95, 107.19, 80.83,59.89, 53.24, 28.18, 13.19, 10.42; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₁N₂O₅ [M+H]⁺: 487.2227, found: 487.2226.

tert-Butyl(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(21)

Colorless solid, ¹H NMR (500 MHz, CDCl₃) δ 8.15 (s, 1H), 6.78 (s, 1H),6.70 (s, 2H), 4.84 (s, 2H), 4.19 (s, 4H), 3.72 (s, 3H), 2.21 (s, 3H),2.19 (s, 3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.62, 155.05,154.99, 148.92, 142.85, 141.48, 136.34, 124.59, 123.75, 120.17, 116.54,115.81, 80.10, 64.24, 64.19, 59.82, 53.68, 28.25, 13.18, 10.37; HRMS(ESI-TOF) m/z Calcd for C₂₂H₂₉N₂O₅ [M+H]⁺: 401.2071, found: 401.2071.

Preparation of Phenol Substrates

2-(Chloromethyl)-3-methylpyridine was synthesized following theliterature. [Narendara et al., Synthetic Commun, 34:1097-1103 (2004)]

General Procedure for Preparation of Phenol Substrates¹:

Phenol derivative (10 mmol) and K₂CO₃ (20 mmol) were added to a 100 mLround bottom flask equipped with a reflux condenser and diluted with 20mL MeCN. Next, 2-(chloromethyl)-3-methylpyridine (12 mmol) was added tothe mixture via syringe and the reaction mixture was stirred at 90° C.for 12 hours. After cooling to room temperature, the mixture was dilutedwith EtOAc and washed with 2 N NaOH three times. The resulting solutionwas dried over sodium sulfate, concentrated by rotatory evaporation andpurified by silica gel chromatography to afford the desired phenolsubstrate Compounds 3a-l.

3-Methyl-2-((m-tolyloxy)methyl)pyridine (3a)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.8 Hz, 1H),7.51 (d, J=7.7 Hz, 1H), 7.21-7.13 (m, 2H), 6.82-6.88 (m, 2H), 6.78 (d,J=7.5 Hz, 1H), 5.20 (s, 2H), 2.43 (s, 3H), 2.33 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 158.70, 154.40, 146.47, 139.42, 138.37, 133.26, 129.11,123.35, 121.79, 115.69, 111.61, 70.73, 21.48, 18.14; HRMS (ESI-TOF) m/zCalcd for C₁₄H₁₅NO [M+H]⁺: 214.1226, found: 214.1228.

2-((3-Methoxyphenoxy)methyl)-3-methylpyridine (3b)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.7 Hz, 1H),7.51 (d, J=7.6 Hz, 1H), 7.23-7.10 (m, 2H), 6.66-6.59 (m, 2H), 6.52 (dd,J=8.3, 2.4 Hz, 1H), 5.19 (s, 2H), 3.78 (s, 3H), 2.42 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 160.75, 159.96, 154.24, 146.57, 138.39, 133.21,129.81, 123.41, 106.93, 106.75, 101.26, 70.83, 55.23, 18.14; HRMS(ESI-TOF) m/z Calcd for C₁₄H₁₆NO₂ [M+H]⁺: 230.1176, found: 230.1180.

2-((3-(1,3-Dioxolan-2-yl)phenoxy)methyl)-3-methylpyridine (3c)

Clear liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.7 Hz, 1H), 7.50 (d,J=7.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.21-7.15 (m, 2H), 7.09 (d, J=7.5 Hz,1H), 7.05 (dd, J=8.2, 2.7 Hz, 1H), 5.81 (s, 1H), 5.23 (s, 2H), 4.16-3.97(m, 4H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.64, 154.04,146.37, 139.42, 138.27, 133.16, 129.31, 123.32, 118.96, 115.54, 112.55,103.32, 103.31, 70.71, 65.09, 18.01; HRMS (ESI-TOF) m/z Calcd forC₁₆H₁₈NO₃ [M+H]⁺: 272.1281, found: 272.1284.

3-Methyl-2-(phenoxymethyl)pyridine (3d)

Clear liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.7 Hz, 1H), 7.49 (d,J=7.6 Hz, 1H), 7.31-7.23 (m, 2H), 7.16 (dd, J=7.7, 4.8 Hz, 1H),7.06-7.00 (m, 2H), 6.94 (t, J=7.6, 1H) 5.20 (s, 2H), 2.41 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 158.63, 154.26, 146.46, 138.30, 133.17, 129.32,123.32, 120.88, 114.76, 70.73, 18.07; HRMS (ESI-TOF) m/z Calcd forC₁₃H₁₄NO [M+H]⁺: 200.1070, found: 200.1073.

3-Methyl-2-((o-tolyloxy)methyl)pyridine (3e)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.9 Hz, 1H),7.52 (d, J=7.2 Hz, 1H), 7.19 (dd, J=7.7, 4.9 Hz, 1H), 7.16-7.10 (m, 2H),7.03 (d, J=8.1 Hz, 1H), 6.86 (t, J=7.4 Hz, 1H), 5.22 (s, 2H), 2.45 (s,3H), 2.22 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 156.74, 154.66, 146.37,138.37, 133.46, 130.62, 126.82, 126.75, 123.35, 120.54, 111.51, 71.16,18.14, 16.23; HRMS (ESI-TOF) m/z Calcd for C₁₄H₁₆NO [M+H]⁺: 214.1226,found: 214.1236.

2-((2-Isopropylphenoxy)methyl)-3-methylpyridine (3f)

Clear liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.4, Hz, 1H), 7.52(d, J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 7.14 (d, J=7.2 Hz, 1H), 7.07 (d,J=8.1 Hz, 1H), 6.94 (t, J=7.4 Hz, 1H), 5.22 (s, 2H) 3.34 (sep, J=6.9 Hz,1H), 2.45 (s, 3H), 1.18 (d, J=6.9 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ155.77, 154.74, 146.44, 138.35, 137.20, 133.43, 126.50, 126.05, 123.38,120.86, 111.81, 71.31, 26.36, 22.90, 18.16; HRMS (ESI-TOF) m/z Calcd forC₁₆H₁₉NO [M+H]⁺: 242.1539, found: 242.1539.

2-((2-Methoxyphenoxy)methyl)-3-methylpyridine (3g)

Yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=4.4 Hz, 1H), 7.37(d, J=7.6 Hz, 1H), 7.04 (dd, J=7.7, 4.8 Hz, 1H), 6.98 (d, J=8.6 Hz, 1H),6.85-6.74 (m, 3H), 5.16 (s, 2H), 3.73 (s, 3H), 2.36 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 154.25, 149.65, 147.97, 146.22, 138.26, 133.36,123.19, 121.41, 120.62, 114.42, 111.69, 71.86, 55.66, 18.02; HRMS(ESI-TOF) m/z Calcd for C₁₄H₁₆NO₂ [M+H]⁺: 230.1176, found: 230.1179.

2-((2-Chlorophenoxy)methyl)-3-methylpyridine (3h)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=4.8 Hz, 1H), 7.52(d, J=7.7 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.23-7.14 (m, 3H), 6.92-6.84(m, 1H), 5.31 (s, 2H), 2.49 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 153.98,153.78, 146.24, 138.62, 133.90, 130.25, 127.65, 123.60, 122.95, 121.59,114.23, 72.02, 18.22; HRMS (ESI-TOF) m/z Calcd for C₁₃H₁₃ClNO [M+H]⁺:234.0680, found: 234.0682.

3-Methyl-2-(((5,6,7,8-tetrahydronaphthalen-1-yl)oxy)methyl)pyridine (3i)

Orange solid, ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.7 Hz, 1H), 7.51 (d,J=7.6 Hz, 1H), 7.19 (dd, J=7.6, 4.8 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H),6.86 (d, J=8.0 Hz, 1H), 6.71 (d, J=7.6 Hz, 1H), 5.21 (s, 2H), 2.75 (t,J=5.1 Hz, 2H), 2.66 (t, J=6.3 Hz, 2H), 2.44 (s, 3H), 1.84-1.68 (m, J=3.3Hz, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 156.34, 154.77, 146.34, 138.49,138.35, 133.49, 126.13, 125.62, 123.32, 121.62, 108.20, 71.06, 29.61,23.10, 22.79, 22.75, 18.20; HRMS (ESI-TOF) m/z Calcd for C₁₇H₂₀NO[M+H]⁺: 254.1539, found: 254.1537.

3-Methyl-2-((naphthalen-1-yloxy)methyl)pyridine (3j)

Orange liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=4.9 Hz, 1H), 8.25(d, J=8.2 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H),7.50-7.42 (m, 3H), 7.38 (t, J=7.9 Hz, 1H), 7.27-7.20 (m, 1H), 7.05 (d,J=7.5 Hz, 1H), 5.42 (s, 2H), 2.48 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ154.40, 154.31, 146.40, 138.54, 134.49, 133.69, 127.43, 126.31, 125.85,125.64, 125.14, 123.52, 122.00, 120.46, 105.40, 71.32, 18.27; HRMS(ESI-TOF) m/z Calcd for C₁₇H₁₆NO [M+H]⁺: 250.1226, found: 250.1228.

2-(((2,3-Dihydro-1H-inden-5-yl)oxy)methyl)-3-methylpyridine (3k)

Yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.8 Hz, 1H), 7.51(d, J=7.5 Hz, 1H), 7.18 (dd, J=7.7, 4.8 Hz, 1H), 7.11 (d, J=8.2 Hz, 1H),6.92 (s, 1H), 6.81 (dd, J=8.0, 2.2 Hz, 1H), 5.18 (s, 2H), 2.92-2.79 (m,4H), 2.43 (s, 3H), 2.06 (p, J=7.4 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ157.60, 154.53, 146.38, 145.64, 138.43, 136.52, 133.33, 124.66, 123.34,112.78, 110.91, 71.05, 33.13, 31.95, 25.77, 18.16; HRMS (ESI-TOF) m/zCalcd for C₁₆H₁₈NO [M+H]⁺: 240.1383, found: 240.1386.

2-((4-Methoxyphenoxy)methyl)-3-methylpyridine (3l)

Light yellow liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.8 Hz, 1H),7.50 (d, J=7.6 Hz, 1H), 7.18 (dd, J=7.7, 4.8 Hz, 1H), 6.96 (d, J=9.0 Hz,2H), 6.82 (d, J=9.0 Hz, 2H), 5.16 (s, 2H), 3.76 (s, 3H), 2.43 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 154.53, 154.00, 152.87, 146.56, 138.37,133.21, 123.36, 115.85, 114.58, 71.55, 55.68, 18.17; HRMS (ESI-TOF) m/zCalcd for C₁₄H₁₆NO₂ [M+H]⁺: 230.1176, found: 230.1179.

Preparation of Other Heterocyclic Substrates

2,4-Dimethyl-3-(2-pyridylmethyl)-3-pentanol (S7)

n-BuLi (1.6 M in hexane, 13 mL, 20 mmol) was slowly added to a solutionof 2-picoline (2.0 mL, 20 mmol) in tetrahydrofuran (20 mL) at −30° C.and the reaction mixture was stirred for 30 minutes. Diisopropyl ketone(3.4 mL, 24 mmol) was then added, the reaction mixture was stirred for 2hours at ambient temperature. Water (30 mL) was added, and the productwas extracted with ethyl acetate (3×20 mL). The combined organic layerwas dried over sodium sulfate, and concentrated in vacuo. Silica gelcolumn purification (Hexane:EtOAc=3:1) gave the pyridyl alcohol S7 (3.5g, 17 mmol) in 85% yield.

Methyl 2-(pyridin-2-ylmethyl)benzoate (4b) [Niwa et al., Angew. Chem.Int. Ed. 46:2643-2645 (2007).]

Cesium carbonate (0.714 g, 2.0 mmol) was placed in a 50-mL two-neckedreaction flask. Cesium carbonate was dried in vacuo with heating with aheat gun for 2 minutes. The flask was then filled with argon usingstandard Schlenk technique. Palladium trifluoroacetate (34 mg, 0.10mmol), tricyclohexylphosphine (53 mg, 0.20 mmol), xylene (10 mL),pyridyl alcohol S7 (0.414 g, 2.0 mmol), and methyl 2-iodobenzoate (576mg, 2.2 mmol) were sequentially added at room temperature. The resultingmixture was heated at reflux for 10 hours. After the mixture was cooledto room temperature, water (30 mL) was added. The product was extractedwith ethyl acetate (30 mL×3). The combined organic layers were driedover sodium sulfate, and concentrated in vacuo. Silica gel columnpurification (Hexane:EtOAc=5:1) gave product Compound 4b (272 mg, 1.2mmol) in 60% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=4.6 Hz, 1H),7.93 (d, J=7.8 Hz, 1H), 7.54 (td, J=7.7, 1.9 Hz, 1H), 7.50-7.42 (m, 1H),7.36-7.28 (m, 2H), 7.13-7.02 (m, 2H), 4.56 (s, 2H), 3.81 (s, 3H); ¹³CNMR (100 MHz, CDCl₃) δ 167.93, 160.81, 149.15, 140.44, 136.28, 132.12,131.98, 130.72, 129.96, 126.54, 122.96, 120.99, 51.91, 42.52; HRMS(ESI-TOF) m/z Calcd for C₁₄H₁₄NO₂ [M+H]⁺: 228.1019, found: 228.1019.

2-Benzyl-3-methylpyridine (4c)

Anhydrous cobalt(II) acetylacetonate (77 mg, 0.30 mmol) was placed in a50 mL flask. Anhydrous dioxane (10 mL) was then added under argon. Afterthe solution became red, benzylmagnesium chloride (2.0 M in THF, 4.5 mL,9.0 mmol) was added at 0° C. The mixture was stirred for about 5 minutesat 25° C. Then, 2-bromo-3-methylpyridine (526 mg, 3.0 mmol) was addeddropwise to the reaction mixture. After stirring for 2 hours at 25° C.,the reaction mixture was poured into water. The products were extractedwith ethyl acetate (3×30 mL) and the combined organic layers were driedover sodium sulfate and concentrated. Purification of the crude productby silica gel column chromatography (Hexane:EtOAc=4:1) provided thecorresponding product Compound 4c (384 mg, 2.1 mmol) in 70% yield. ¹HNMR (400 MHz, CDCl₃) δ 8.42 (d, J=4.6 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H),7.25 (t, J=7.5 Hz, 2H), 7.22-7.13 (m, 3H), 7.07 (dd, J=7.6, 4.9 Hz, 1H),4.19 (s, 2H), 2.24 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 158.76, 146.74,138.99, 137.96, 131.70, 128.61, 128.33, 126.04, 121.66, 42.21, 18.92;HRMS (ESI-TOF) m/z Calcd for C₁₃H₁₄N [M+H]⁺: 184.1121, found: 184.1121.

2-Benzyl-5-methylpyridine (4d) [Ohmiya et al., Chem. Lett., 33:1240-1241(2004).]

Anhydrous cobalt(II) acetylacetonate (77 mg, 0.30 mmol) was placed in a50 mL flask. Anhydrous dioxane (10 mL) was then added under argon. Afterthe solution became red, benzylmagnesium chloride (2 M in THF, 4.5 mL,9.0 mmol) was added at 0° C. The mixture was stirred for about 5 minutesat 25° C. Then, 2-bromo-5-methylpyridine (526 mg, 3.0 mmol) was addeddropwise to the reaction mixture. After being stirred for 2 hours at 25°C., the reaction mixture was poured into water. The products wereextracted with ethyl acetate (30 mL×3). The combined organic layers weredried over sodium sulfate and concentrated. Purification of the crudeproduct by silica gel column chromatography (Hexane:EtOAc=4:1) providedthe corresponding product Compound 4d (455 mg, 2.4 mmol) in 83% yield.¹H NMR (400 MHz, CDCl₃) δ 8.52 (s, 1H), 7.57-7.50 (m, 1H), 7.49-7.38 (m,4H), 7.38-7.32 (m, 1H), 7.15 (d, J=7.9 Hz, 1H), 4.27 (s, 2H), 2.43 (s,3H); ¹³C NMR (100 MHz, cdcl₃) δ 157.96, 149.60, 139.77, 137.09, 130.43,128.98, 128.49, 126.22, 122.53, 44.18, 17.98; HRMS (ESI-TOF) m/z Calcdfor C₁₃H₁₄N [M+H]⁺: 184.1121, found: 184.1121.

2-benzylpyrimidine (4e)

According to procedure for Compound 4c, Compound 4e was afforded in 83%yield using 2-(bromomethyl)pyrimidine. ¹H NMR (400 MHz, CDCl₃) δ 8.68(d, J=4.9 Hz, 2H), 7.36 (d, J=7.6 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.22(t, J=7.3 Hz, 1H), 7.12 (t, J=4.9 Hz, 1H), 4.30 (s, 2H); ¹³C NMR (150MHz, CDCl₃) δ 170.03, 157.29, 138.19, 129.12, 128.52, 126.57, 118.63,46.05; HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₁N₂ [M+H]⁺: 171.0917, found:171.0916.

2-Benzylpyrazine (4f)

According to procedure for Compound 4c, Compound 4f was afforded in 70%yield using 2-(bromomethyl)pyrazine. ¹H NMR (400 MHz, CDCl₃) δ 8.50 (t,J=2.0 Hz, 1H), 8.47 (s, 1H), 8.40 (d, J=2.5 Hz, 1H), 7.36-7.20 (m, 5H),4.17 (s, 2H); ¹³C NMR (100 MHz, cdcl₃) δ 156.44, 144.73, 144.04, 142.34,138.08, 128.96, 128.72, 126.72, 41.94; HRMS (ESI-TOF) m/z Calcd forC₁₁H₁₁N₂ [M+H]⁺: 171.0917, found: 171.0917.

1-Benzyl-1H-pyrazole (4g) [Kumpulainen et al., Adv. Synth. Catal.356:1555-1561 (2014).]

A round bottomed flask was charged with pyrazole (504 mg, 12.6 mmol),benzyl bromide (1.0 mL, 8.4 mmol), potassium carbonate (1.738 g, 12.6mmol), potassium iodide (70 mg, 0.043 mmol) and dimethylformamide (10mL). The mixture was heated to 80° C. for 13 hours. The reaction mixturewas allowed to cool to room temperature and poured into a beakercontaining water (20 mL) and ethyl acetate (50 mL). Next, the phaseswere separated and aqueous phase was extracted with ethyl acetate (50mL). Combined organic extracts were dried with anhydrous sodium sulfateand solvents were evaporated. Purification by silica gel columnchromatography(Hexane:EtOAc=20:1) provided the corresponding product(796 mg, 5.0 mmol) in 60% yield. ¹H NMR (600 MHz, CDCl₃) δ 7.58 (d,J=1.9 Hz, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.39-7.34 (m, 2H), 7.34-7.30 (m,1H), 7.26-7.22 (m, 2H), 6.31 (t, J=2.1 Hz, 1H), 5.35 (s, 2H); ¹³C NMR(150 MHz, CDCl₃) δ 139.43, 136.59, 129.12, 128.69, 127.89, 127.52,105.86, 55.82; HRMS (ESI-TOF) m/z Calcd for C₁₀H₁₁N₂ [M+H]⁺: 159.0917,found: 159.0917.

N-phenyl-N-(pyridin-2-yl)acetamide (4h) [Wang et al., Tetrahedron Lett55:7121-7123 (2014).]

A 10 mL flask equipped with a magnetic stir bar and a Teflon valve wascharged with CuI (19 mg, 1 mol %), pyridin-2-amine (1.41 g, 15 mmol),and KOtBu (2.12 g, 20 mmol). The tube was evacuated and backfilled withargon. Under a counter flow of argon, 1,4-dioxane (25 mL) andbromobenzene (1.57 g, 10 mmol) were added via syringe and the tube wassealed. The reaction mixture was allowed to stir at 110° C. for 24hours. The mixture was cooled to room temperature and 5.0 mL of brinewas added. Subsequently, the mixture was extracted with ethyl acetate.The organic layers were collected, dried over sodium sulfate, filteredand the solvent was removed under vacuum. The residue was purified bycolumn chromatography on silica gel (hexanes EtOAc=8:1) to give thesecondary amine as a colorless solid (1.35 g, 8.2 mmol) in 82% yield.

NaH (60% in mineral oil, 50 mg, 1.2 mmol) was added into the solution ofsecondary amine (170 mg, 10 mmol) in THF. The reaction mixture wasstirred at room temperature for 30 minutes. Then acetyl chloride (110mg, 1.5 mmol) was added and the reaction was monitored by TLC. Uponcompletion, the mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic phases were washed with brine and dried over sodiumsulfate and concentrated. The crude product was purified by columnchromatography on silica gel (Hexanes:EtOAc=20:1) to give the titleproduct Compound 4h (174 mg, 0.85 mmol) in 85% yield. ¹H NMR (600 MHz,CDCl₃) δ 8.43 (dd, J=4.9, 1.9 Hz, 1H), 7.71 (td, J=7.8, 2.0 Hz, 1H),7.46 (d, J=8.4 Hz, 1H), 7.44-7.38 (m, 2H), 7.33 (d, J=7.5 Hz, 1H),7.32-7.27 (m, 2H), 7.13 (dd, J=7.0, 5.1 Hz, 1H), 2.11 (s, 3H); ¹³C NMR(150 MHz, CDCl₃) δ 170.89, 155.18, 148.74, 141.96, 137.86, 129.38,128.31, 127.54, 121.38, 121.13, 24.21; HRMS (ESI-TOF) m/z Calcd forC₁₃H₁₃N₂O [M+H]⁺: 213.1022, found: 213.1021.

tert-Butyl phenyl (pyrimidin-2-yl) carbamate (4i) [Qian et al., Eur. J.Org. Chem. 4837-4843 (2014).]

To an oven-dried flask containing aniline (1.39 g, 15.0 mmol) was addeda solution of 2-chloro-pyrimidine (1.14 g, 10.0 mmol) and acetic acid(0.6 g, 10 mmol) in 1,4-dioxane (30.0 mL). The reaction mixture wasstirred at 110° C. overnight. Upon completion, the mixture was extractedwith CH₂Cl₂ (3×30 mL). The combined organic phases were washed withbrine, dried over sodium sulfate and concentrated. The crude product waspurified by column chromatography on silica gel (hexanes:EtOAc=5:1) togive the secondary amine as a colorless solid (1.28 g, 7.5 mmol) in 75%yield.

The secondary amine (513 mg, 3.0 mmol) was dissolved in anhydrous DMF(30 mL), and the solution was cooled to 0° C. in an ice/water bath.Sodium hydride (132 mg, 60% suspension in oil, 3.3 mmol) was added inportions. The suspension was stirred vigorously for an additional 20minutes while maintaining the temperature below 5° C. and then (Boc)₂O(719 mg, 3.3 mmol) was added dropwise. After stirring for 30 minutes,the reaction mixture was brought to room temperature over a 1 hourperiod before water (5.0 mL) was added. The mixture was then dilutedwith water (20 mL) and extracted with ethyl acetate (3×30 mL). Theorganic layer was separated and extracted with water, 0.1 M HCl, sat.aqueous NaHCO₃ solution, and brine, then dried and concentrated. Theresulting residue was then purified by silica gel chromatography(Hexanes:EtOAc=10:1) to afford Compound 4i (650 mg, 80%) as a clear,colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 8.66 (d, J=4.8 Hz, 2H), 7.44-7.35 (m, 2H),7.32-7.26 (m, 1H), 7.25-7.20 (m, 2H), 7.04 (t, J=4.8 Hz, 1H), 1.45 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 161.35, 158.21, 153.16, 141.25, 128.95,127.69, 126.84, 117.14, 82.04, 28.05; HRMS (ESI-TOF) m/z Calcd forC₁₅H₁₈N₃O₂ [M+H]⁺: 272.1394, found: 272.1394.

1-Benzyl-1H-indazole and 2-Benzyl-2H-indazole [Shumeiko et al., Russ. J.Org. Chem. 42:294-295 (2006).]

A round-bottom flask was charged with indazole (1.18 g, 10.0 mmol),benzyl bromide (1.44 mL, 10.0 mmol), potassium hydroxide (0.56 g, 10.0mmol), tetrabutylammonium chloride (189 mg, 0.5 mmol) and toluene (50mL). The mixture was heated to 110° C. overnight (about 18 hours). Thereaction mixture was allowed to cool to room temperature and poured intoa beaker containing water (20 mL) and ethyl acetate (50 mL). Phases wereseparated and the aqueous phase was extracted with ethyl acetate (50mL). Combined organic extracts were dried over anhydrous sodium sulfateand solvents were evaporated. The resulting residue was then purified bysilica gel column chromatography (Hexanes:EtOAc=20:1-10:1) to providethe corresponding 1-benzyl-1H-indazole 4k (1.1 g, 5.5 mmol) in 55% yieldand 2-benzyl-2H-indazole 4k′ (561 mg, 2.7 mmol) in 27% yield.

2-Benzyl-2H-indazole (4j)

¹H NMR (400 MHz, CDCl₃) δ 7.89-7.85 (m, 1H), 7.73 (d, J=8.8 Hz, 1H),7.61 (d, J=8.4 Hz, 1H), 7.38-7.30 (m, 3H), 7.30-7.23 (m, 3H), 7.06 (dd,J=8.3, 6.7 Hz, 1H), 5.58 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 148.90,135.73, 128.87, 128.32, 127.92, 125.91, 122.78, 122.06, 121.71, 120.09,117.50, 57.47; HRMS (ESI-TOF) m/z Calcd for C₁₄H₁₃N₂ [M+H]⁺: 209.1073,found: 209.1074.

1-Benzyl-1H-indazole (4k)

¹H NMR (600 MHz, CDCl₃) δ 8.04 (d, J=0.9 Hz, 1H), 7.74 (dt, J=8.1, 1.0Hz, 1H), 7.36-7.31 (m, 2H), 7.30-7.26 (m, 2H), 7.26-7.23 (m, 1H),7.21-7.19 (m, 1H), 7.19-7.17 (m, 1H), 7.15-7.12 (m, 1H), 5.60 (s, 2H);¹³C NMR (150 MHz, CDCl₃) δ 139.52, 136.86, 133.36, 128.69, 127.70,127.14, 126.35, 124.34, 121.12, 120.61, 109.26, 52.95; HRMS (ESI-TOF)m/z Calcd for C₁₄H₁₃N₂ [M+H]⁺: 209.1073, found: 209.1074.

1-Benzylisoquinoline (41)

Anhydrous cobalt(II) acetylacetonate (77 mg, 0.30 mmol) was placed in a50 mL flask. Anhydrous 1,4-dioxane (10 mL) was then added under argon.After the solution became red, benzylmagnesium chloride (2 M in THFsolution, 4.5 mL, 9.0 mmol) was added at 0° C. The mixture was stirredfor about 5 minutes at 25° C. Next, 2-chloroquinoline (491 mg, 3.0 mmol)was added dropwise to the reaction mixture. After being stirred for 2hours at 25° C., the reaction mixture was poured into water. Theproducts were extracted with ethyl acetate (3×30 mL). The combinedorganic layers were dried over sodium sulfate and concentrated.Purification of the crude product by silica gel column chromatography(Hexanes:EtOAc=4:1) provided the corresponding product Compound 41 (328mg, 1.5 mmol) in 50% yield. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.5 Hz,1H), 7.99 (d, J=8.5 Hz, 1H), 7.73 (d, J=8.2 Hz, 1H), 7.68 (t, J=7.6 Hz,1H), 7.47 (t, J=7.5 Hz, 1H), 7.33-7.25 (m, 4H), 7.25-7.16 (m, 2H), 4.34(s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 161.14, 147.74, 139.15, 136.42,129.41, 129.15, 128.92, 128.56, 127.44, 126.70, 126.42, 125.91, 121.46,45.50; HRMS (ESI-TOF) m/z Calcd for C₁₆H₁₄N [M+H]⁺: 220.1121, found:220.1121.

Synthesis of Substrates Bearing Different Protecting Groups

S3a-3i were synthesized following a similar procedure to makesubstrate 1. The protected amines were prepared as previously described.[Pialat et al., Org. Lett. 15:1764-1767 (2013); Brasche et al., Org.Lett. 10:2207-2210 (2008); Wipf et al., Org. Lett. 10:4383-4386 (2008);Imanishi et al., Adv. Synth. Catal. 354:771-776 (2012); Gawande et al.,Green Chem. 13:3355-3359 (2011); Johnson et al., J. Org. Chem.68:5300-5309 (2003); and Le Pera et al., Tetrahedron 62:100-6106(2006).]

N-(Pyridin-2-ylmethyl)-N-(m-tolyl) acetamide (S3a)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=4.9 Hz, 1H), 7.64(td, J=7.7, 1.8 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.20 (t, J=7.7 Hz, 1H),7.14 (dd, J=7.5, 5.0 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 6.97 (s, 1H), 6.92(d, J=7.9 Hz, 1H), 5.02 (s, 2H), 2.31 (s, 3H), 1.95 (s, 3H); ¹³C NMR(150 MHz, CDCl₃) δ 170.69, 157.40, 149.02, 143.16, 139.55, 136.44,129.22, 128.59, 128.31, 124.85, 122.40, 122.03, 54.87, 22.57, 21.20;HRMS (ESI-TOF) m/z Calcd for C₁₅H₁₇N₂O [M+H]⁺: 241.1335, found:241.1335.

N-(Pyridin-2-ylmethyl)-N-(m-tolyl)pivalamide (S3b)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J=4.8 Hz, 1H), 7.65(td, J=7.7, 1.8 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.21-7.05 (m, 3H), 6.99(s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.95 (s, 2H), 2.30 (s, 3H), 1.07 (s,9H); ¹³C NMR (100 MHz, CDCl₃) δ 177.81, 157.95, 148.84, 143.71, 138.86,136.35, 130.05, 128.62, 128.59, 126.50, 122.23, 121.82, 58.48, 40.96,29.46, 21.17; HRMS (ESI-TOF) m/z Calcd for C₁₈H₂₃N₂O [M+H]⁺: 283.1805,found: 283.1805.

tert-Butyl (pyridin-2-ylmethyl)(m-tolyl)carbamate (S3c)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=4.6 Hz, 1H), 7.66(td, J=7.7, 1.8 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.20-7.09 (m, 3H), 7.06(d, J=8.0 Hz, 1H), 6.96 (d, J=7.4 Hz, 1H), 4.96 (s, 2H), 2.30 (s, 3H),1.40 (s, 9H); ¹³C NMR (100 MHz, cdcl₃) δ 158.73, 154.67, 149.09, 142.87,138.39, 136.46, 128.35, 126.41, 126.36, 122.80, 121.79, 120.73, 80.59,55.92, 28.17, 21.33; HRMS (ESI-TOF) m/z Calcd for C₁₈H₂₃N₂O₂ [M+H]⁺:299.1754, found: 299.1754.

Benzyl (pyridin-2-ylmethyl)(m-tolyl)carbamate (S3d)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=4.7 Hz, 1H), 7.60(t, J=7.6 Hz, 1H), 7.33-7.25 (m, 4H), 7.25-7.11 (m, 4H), 7.09 (s, 1H),7.05 (d, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 5.18 (s, 2H), 5.00 (s,2H), 2.29 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 157.83, 155.60, 149.20,142.14, 138.65, 136.52, 136.40, 128.57, 128.29, 127.80, 127.63, 127.18,126.94, 123.26, 122.00, 121.25, 67.37, 56.10, 21.29; HRMS (ESI-TOF) m/zCalcd for C₂₁H₂₁N₂O₂ [M+H]⁺: 333.1598, found: 333.1598.

2,2,2-Trichloroethyl (pyridin-2-ylmethyl)(m-tolyl)-carbamate (S3e)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=4.8 Hz, 1H), 7.66(t, J=7.7 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.25-7.06 (m, 4H), 7.03 (d,J=7.5 Hz, 1H), 5.05 (s, 2H), 4.79 (s, 2H), 2.31 (s, 3H); ¹³C NMR (150MHz, CDCl₃) δ 157.16, 154.02, 149.35, 142.16, 141.00, 138.78, 136.61,128.65, 127.70, 126.36, 123.82, 122.24, 121.66, 95.39, 77.25, 77.04,76.83, 75.20, 56.43, 21.30; HRMS (ESI-TOF) m/z Calcd for C₁₆H₁₆Cl₃N₂O₂[M+H]⁺: 373.0272, found: 373.0271.

(9H-Fluoren-9-yl)methyl (pyridin-2-ylmethyl)(m-tolyl)-carbamate (S3f)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=4.8 Hz, 1H),7.69 (d, J=7.6 Hz, 2H), 7.62 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.5 Hz, 2H),7.30-7.21 (m, 3H), 7.21-7.12 (m, 4H), 7.11-7.02 (d, J=6.3 Hz, 2H), 6.99(d, J=6.9 Hz, 1H), 4.97 (s, 2H), 4.45 (d, J=7.0 Hz, 2H), 4.10 (t, J=7.0Hz, 1H), 2.32 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 157.65, 155.75,149.23, 143.71, 141.89, 141.19, 138.84, 136.57, 128.73, 127.51, 126.86,125.09, 124.26, 122.07, 121.54, 119.78, 67.60, 56.08, 47.11, 21.32; HRMS(ESI-TOF) m/z Calcd for C₂₈H₂₅N₂O₂ [M+H]⁺: 421.1911, found: 421.1911.

N-(Pyridin-2-ylmethyl)-N-(m-tolyl)methanesulfonamide (S3g)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=4.7 Hz, 1H),7.64 (td, J=7.7, 1.8 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H), 7.24-7.11 (m, 4H),7.06 (d, J=7.3 Hz, 1H), 5.01 (s, 2H), 3.04 (s, 3H), 2.30 (s, 3H); ¹³CNMR (150 MHz, CDCl₃) δ 156.70, 149.06, 139.37, 136.70, 129.07, 128.82,128.75, 124.96, 122.46, 122.35, 56.53, 38.13, 21.28; HRMS (ESI-TOF) m/zCalcd for C₁₄H₁₇N₂O₂S [M+H]⁺: 277.1005, found: 277.1005.

1,1,1-Trifluoro-N-(pyridin-2-ylmethyl)-N-(m-tolyl)-methanesulfonamide(S3h)

Yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=4.8 Hz, 1H), 7.68(td, J=7.7, 1.8 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.24-7.15 (m, 2H),7.14-7.04 (m, 3H), 5.07 (s, 2H), 2.30 (s, 3H); ¹³C NMR (150 MHz, CDCl₃)δ 154.65, 149.38, 139.53, 136.84, 129.97, 129.42, 129.10, 125.91,122.99, 122.61, 120.46 (q, J=324.2 Hz), 58.52, 21.22; ¹⁹F NMR (376 MHz,CDCl₃) δ −73.54; HRMS (ESI-TOF) m/z Calcd for C₁₄H₁₄F₃N₂O₂S [M+H]⁺:331.0723, found: 331.0723.

4-Nitro-N-(pyridin-2-ylmethyl)-N-(m-tolyl)benzenesulfonamide (S3i)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J=4.7 Hz, 1H),8.30 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 7.66 (td, J=7.7, 1.7 Hz,1H), 7.52 (d, J=7.9 Hz, 1H), 7.17-7.09 (m, 2H), 7.06 (d, J=7.6 Hz, 1H),6.96 (s, 1H), 6.83 (d, J=7.7 Hz, 1H), 4.93 (s, 2H), 2.26 (s, 3H); ¹³CNMR (150 MHz, CDCl₃) δ 155.77, 150.05, 149.06, 144.00, 139.35, 138.44,136.76, 129.34, 129.22, 128.96, 125.09, 123.93, 122.62, 122.44, 56.87,21.22; HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₈N₃O₄S [M+H]⁺: 384.1013, found:384.1013.

Synthesis of Substrates Bearing Different Directing Groups

S5a-5e were synthesized following a similar procedure to preparesubstrate 1.

tert-Butyl (quinolin-2-ylmethyl)(m-tolyl)carbamate (S5a)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.15 (d, J=8.5 Hz, 1H),8.02 (d, J=8.5 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.72-7.66 (m, 1H),7.55-7.47 (m, 2H), 7.21-7.12 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 6.95 (d,J=7.3 Hz, 1H), 5.13 (s, 2H), 2.29 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 159.14, 154.91, 147.63, 142.84, 138.47, 136.63, 129.51,128.97, 128.42, 127.53, 127.16, 126.62, 126.57, 126.09, 123.04, 118.88,80.73, 56.48, 28.22, 21.37; HRMS (ESI-TOF) m/z Calcd for C₂₂H₂₅N₂O₂[M+H]⁺: 349.1911, found: 349.1911.

tert-Butyl (quinolin-2-ylmethyl)(m-tolyl)carbamate (S5b)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 7.55 (t, J=7.7 Hz, 1H),7.19-7.10 (m, 3H), 7.07 (d, J=8.1 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.95(d, J=7.4 Hz, 1H), 4.92 (s, 2H), 2.51 (s, 3H), 2.30 (s, 3H), 1.40 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 158.07, 157.70, 154.71, 142.95, 138.32,136.68, 128.31, 126.36, 126.32, 122.76, 121.23, 117.34, 80.53, 55.96,28.18, 24.34, 21.34; HRMS (ESI-TOF) m/z Calcd for C₁₉H₂₅N₂O₂ [M+H]⁺:313.1911, found: 313.1911.

tert-Butyl ((3-methylpyridin-2-yl)methyl)(m-tolyl)-carbamate (S5c)

Light yellow solid, ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=4.6 Hz, 1H),7.38 (d, J=7.6 Hz, 1H), 7.16-7.00 (m, 4H), 6.92 (d, J=7.4 Hz, 1H), 4.93(s, 2H), 2.30 (s, 3H), 2.27 (s, 3H), 1.37 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 155.32, 154.74, 146.51, 142.81, 138.05, 137.46, 130.61, 128.06,126.85, 126.26, 123.39, 121.90, 80.10, 53.44, 28.16, 21.29, 18.00; HRMS(ESI-TOF) m/z Calcd for C₁₉H₂₅N₂O₂ [M+H]⁺: 313.1911, found: 313.1911.

tert-Butyl((3-methoxy-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)(m-tolyl)carbamate(S5d)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.31 (d, J=5.6 Hz, 1H),7.16-6.98 (m, 3H), 6.92 (d, J=7.4 Hz, 1H), 6.59 (d, J=5.6 Hz, 1H), 4.93(s, 2H), 4.37 (q, J=7.9 Hz, 2H), 2.27 (s, 3H), 2.20 (s, 3H), 1.38 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 161.13, 157.09, 154.73, 147.71, 142.75,138.09, 128.08, 126.81, 126.30, 123.38, 122.98 (q, J=278.34 Hz), 119.92,105.10, 80.21, 65.31 (q, J=36.2 Hz), 53.37, 28.18, 21.30, 9.64; ¹⁹F NMR(376 MHz, CDCl₃) δ −74.21; HRMS (ESI-TOF) m/z Calcd forC₂₁H₂₆F₃N₂O₄[M+H]⁺: 411.1890, found: 411.1890.

tert-Butyl ((3,4-dimethoxypyridin-2-yl)methyl)(m-tolyl)-carbamate (S5e)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.21 (d, J=5.5 Hz, 1H),7.19-7.03 (m, 3H), 6.91 (d, J=7.0 Hz, 1H), 6.74 (d, J=5.5 Hz, 1H), 4.97(s, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.28 (s, 3H), 1.39 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 157.99, 154.90, 151.47, 145.59, 143.22, 142.90,138.01, 128.04, 126.85, 126.11, 123.41, 106.49, 79.97, 60.41, 55.54,50.72, 28.24, 21.33; HRMS (ESI-TOF) m/z Calcd for C₂₀H₂₇N₂O₄ [M+H]⁺:359.1965, found: 359.1964.

Synthesis of MPAHP Ligands

Ligands L12-19 were synthesized from commercially available amines S9.In cases where the amines were not commercially available, the freeamines S9 were synthesized by the reduction of the nitro group.

Reduction:

In a 100 mL round bottom flask, S8 (10.0 mmol), 10% Pd/C (1.0 mmol) wereadded and the flask was sealed with a rubber stopper. Next, 50 mLmethanol was added under nitrogen. The nitrogen was removed and theflask was back filled with hydrogen three times. Then a hydrogen balloonwas left on the flask and the reaction mixture was stirred for 16 hoursat room temperature. After the 16 hours, the reaction mixture wasfiltered through a pad of Celite® and the solvent was evaporated toobtain the pure amino product in quantitative yields.

Acetyl Protection:

In a 50 mL round bottom flask, S9 (8.0 mmol), acetic anhydride (9.6mmol) and 20 mL toluene were added and the reaction mixture was refluxedfor 16 hours. The solvent was removed and the residue was washed withdiethyl ether (5.0 mL) twice to remove impurities. The left over residuewas recrystallized with methanol to obtain the product.

N-(2-Hydroxypyridin-3-yl)acetamide (L12)

Black solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 9.18 (s, 1H),8.20 (dd, J=7.4, 1.8 Hz, 1H), 7.06 (dd, J=6.6, 1.9 Hz, 1H), 6.18 (t,J=6.9 Hz, 1H), 2.11 (s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ 169.30,157.25, 129.45, 127.53, 123.25, 105.20, 24.00; HRMS (ESI-TOF) m/z Calcdfor C₇H₉N₂O₂ [M+H]⁺: 153.0659, found: 153.0659.

tert-Butyl (2-hydroxypyridin-3-yl)carbamate (L13)

Beige solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.91 (s, 1H), 7.79 (dd, J=7.1,2.0 Hz, 1H), 7.68 (s, 1H), 7.03 (dd, J=6.6, 1.8 Hz, 1H), 6.21 (t, J=6.9Hz, 1H), 1.45 (s, 9H); ¹³C NMR (150 MHz, DMSO-d₆) δ 157.01, 152.11,129.01, 126.59, 120.66, 105.35, 80.01, 27.88; HRMS (ESI-TOF) m/z Calcdfor C₁₀H₁₅N₂O₃ [M+H]⁺: 211.1077, found: 211.1077.

N-(2-Hydroxy-5-(trifluoromethyl)pyridin-3-yl)acetamide (L14)

Beige solid, ¹H NMR (400 MHz, DMSO-d₆) δ 12.51 (s, 1H), 9.55 (s, 1H),8.41 (d, J=2.6 Hz, 1H), 7.69-7.61 (m, 1H), 2.15 (s, 3H); ¹³C NMR (150MHz, DMSO-d₆) δ 170.23, 157.16, 130.11, 127.64 (q, J=4.7 Hz), 123.86 (q,J=269.5 Hz), 116.81, 107.23 (q, J=34.1 Hz), 24.00; ¹⁹F NMR (376 MHz,DMSO-d₆) δ −60.60; HRMS (ESI-TOF) m/z Calcd for C₈H₈F₃N₂O₂ [M+H]⁺:221.0532, found: 221.0532.

N-(2-Hydroxy-6-(trifluoromethyl)pyridin-3-yl)acetamide (L15)

Beige solid, ¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.46 (d, J=7.9Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 2.15 (s, 3H); ¹³C NMR (150 MHz,DMSO-d₆) δ 169.98, 155.31, 132.92, 127.74, 124.99, 121.16 (q, J=272.7Hz), 110.60, 23.99; ¹⁹F NMR (376 MHz, DMSO-d₆) 5-65.22; HRMS (ESI-TOF)m/z Calcd for C₈H₈F₃N₂O₂ [M+H]⁺: 221.0532, found: 221.0532.

N-(2-Hydroxy-5-methylpyridin-3-yl)acetamide (L16)

Colorless solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.68 (s, 1H), 9.15 (s,1H), 8.11 (d, J=2.4 Hz, 1H), 6.85 (dd, J=2.3, 1.2 Hz, 1H), 2.10 (s, 3H),2.01 (d, J=1.1 Hz, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ 169.27, 156.32,128.89, 125.50, 124.50, 113.60, 24.03, 17.10; HRMS (ESI-TOF) m/z Calcdfor C₈H₁₁N₂O₂ [M+H]⁺: 167.0815, found: 167.0815.

N-(2-Hydroxy-4-methylpyridin-3-yl)acetamide (L17)

Colorless solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 9.08 (s,1H), 7.16 (d, J=6.7 Hz, 1H), 6.06 (d, J=6.7 Hz, 1H), 1.99 (s, 3H), 1.97(s, 3H); ¹³C NMR (150 MHz, DMSO-d₆) δ 167.97, 159.90, 145.60, 130.99,125.64, 107.86, 22.75, 18.49; HRMS (ESI-TOF) m/z Calcd for C₈H₁₁N₂O₂[M+H]⁺: 167.0815, found: 167.0815.

N-(4-Hydroxy-2,6-dimethylpyridin-3-yl)acetamide (L18)

Colorless solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.12 (s, 1H), 8.84 (s,1H), 5.91 (s, 1H), 2.17 (s, 3H), 2.04 (s, 3H), 1.96 (s, 3H); ¹³C NMR(150 MHz, DMSO-d₆) δ 174.23, 168.04, 145.41, 142.63, 122.97, 113.63,22.77, 18.35, 16.19; HRMS (ESI-TOF) m/z Calcd for C₉H₁₃N₂O₂ [M+H]⁺:181.0972, found: 181.0972.

N-(2-Hydroxyquinolin-3-yl)acetamide (L19)

Beige solid, ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 9.43 (s, 1H),8.63 (s, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.43-7.35 (m, 1H), 7.28 (d, J=8.1Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 2.18 (s, 3H); ¹³C NMR (150 MHz,DMSO-d₆) δ 169.70, 157.43, 134.32, 128.76, 128.10, 127.25, 122.41,120.49, 119.72, 114.87, 24.11; HRMS (ESI-TOF) m/z Calcd for C₁₁H₁₁N₂O₂[M+H]⁺: 203.0815, found: 203.0815.

To a solution of amine (2.0 mmol) and 1-adamantanecarbonyl chloride(437.1 mg, 2.2 mmol) in DCM (10.0 mL) was added triethylamine (0.56 mL,4.0 mmol) at 0° C.

The mixture was allowed to warm to room temperature and stirred at roomtemperature. After the reaction was completed, the solvent was removedunder vacuum and the resulting residue was then purified by silica gelchromatography to afford L24 as a colorless solid.

(3r,5r,7r)-N-(2-Hydroxy-5-(trifluoromethyl)pyridin-3-yl)adamantane-1-carboxamide(L24)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 12.80 (brs, 1H), 8.76 (d,J=2.4 Hz, 1H), 8.56 (s, 1H), 7.50 (s, 1H), 2.13 (s, 3H), 2.07-1.90 (m,6H), 1.84-1.69 (m, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 177.36, 159.30,129.79, 125.78, 125.32, 125.28, 125.24, 125.20, 123.99, 122.20, 120.41,119.15, 112.65, 112.41, 112.18, 111.95, 42.05, 39.10, 38.74, 36.43,36.32, 28.00, 27.86; HRMS (ESI-TOF) m/z Calcd for C₁₇H₂₀F₃N₂O₂ [M+H]⁺:341.1471, found: 341.1474.

2,2,2-Trifluoro-N-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)acetamide(L25)

Colorless solid, ¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (brs, 2H), 8.12 (d,J=2.6 Hz, 1H), 7.98-7.88 (m, 1H); ¹³C NMR (150 MHz, DMSO-d₆) δ 157.45,155.22 (q, J=37.5 Hz), 132.36 (q, J=5.3 Hz), 126.82, 124.67 (q, J=3.0Hz), 123.52 (q, J=269.6 Hz), 115.37 (q, J=286.2 Hz), 106.75 (q, J=34.5Hz); HRMS (ESI-TOF) m/z Calcd for C₈H₅F₆N₂O₂ [M+H]⁺: 275.0250, found:275.0250.

Condition Screening

Ligand Screened

Methyl3′-methyl-5′-(N-(pyridin-2-ylmethyl)acetamido)-[1,1′-biphenyl]-2-carboxylate(S4a)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.50 (d, J=4.8 Hz, 1H), 7.82(d, J=7.7 Hz, 1H), 7.67 (t, J=7.5 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.41(t, J=6.9 Hz, 2H), 7.26 (d, J=6.9 Hz, 1H), 7.20-7.13 (m, 1H), 7.07 (s,1H), 6.98 (s, 1H), 6.90 (s, 1H), 5.05 (s, 2H), 3.60 (s, 3H), 2.36 (s,3H), 2.02 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 170.85, 168.42, 157.30,148.81, 142.85, 142.64, 141.45, 139.37, 136.77, 131.33, 130.56, 130.50,129.91, 128.59, 127.47, 127.03, 125.32, 122.39, 122.14, 54.85, 51.94,22.64, 21.29; HRMS (ESI-TOF) m/z Calcd for C₂₃H₂₃N₂O₃ [M+H]⁺: 375.1703,found: 375.1703.

Methyl3′-methyl-5′-(N-(pyridin-2-ylmethyl)pivalamido)-[1,1′-biphenyl]-2-carboxylate(S4b)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=4.4 Hz, 1H), 7.81(d, J=7.7 Hz, 1H), 7.66 (td, J=7.8, 1.8 Hz, 1H), 7.49 (t, J=7.2 Hz, 1H),7.43-7.37 (m, 2H), 7.21-7.11 (m, 2H), 7.04-6.98 (m, 2H), 6.92 (s, 1H),4.98 (s, 2H), 3.56 (s, 3H), 2.34 (s, 3H), 1.12 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 177.91, 168.61, 157.94, 148.84, 143.60, 142.35, 141.50,138.56, 136.59, 131.27, 130.63, 130.53, 129.88, 128.84, 128.73, 127.43,126.57, 122.25, 121.94, 58.58, 51.89, 41.09, 29.60, 21.26; HRMS(ESI-TOF) m/z Calcd for C₂₆H₂₉N₂O₃ [M+H]⁺: 417.2173, found: 417.2172.

Methyl3′-((tert-butoxycarbonyl)(pyridin-2-ylmethyl)-amino)-5′-methyl-[1,1′-biphenyl]-2-carboxylate(S4c)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.54 (d, J=4.8 Hz, 1H), 7.76(d, J=7.7 Hz, 1H), 7.69 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.5 Hz, 1H),7.41-7.35 (m, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.22-7.15 (m, 1H), 7.11 (s,1H), 7.06 (s, 1H), 6.93 (s, 1H), 4.99 (s, 2H), 3.57 (s, 3H), 2.34 (s,3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 169.09, 158.62, 154.60,148.87, 142.66, 141.80, 141.58, 138.13, 136.77, 131.10, 130.92, 130.55,129.61, 127.14, 126.53, 125.36, 123.13, 121.90, 120.81, 80.68, 55.92,51.89, 28.18, 21.38; HRMS (ESI-TOF) m/z Calcd for C₂₆H₂₉N₂O₄ [M+H]⁺:433.2122, found: 433.2122.

Methyl3′-(((benzyloxy)carbonyl)(pyridin-2-ylmethyl)-amino)-5′-methyl-[1,1′-biphenyl]-2-carboxylate(S4d)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d, J=4.9 Hz, 1H), 7.77(d, J=7.7 Hz, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H), 7.38(t, J=7.6 Hz, 1H), 7.35-7.18 (m, 7H), 7.18-7.12 (m, 1H), 7.09 (s, 1H),7.05 (s, 1H), 6.96 (s, 1H), 5.18 (s, 2H), 5.03 (s, 2H), 3.50 (s, 3H),2.33 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 169.02, 157.82, 155.59, 149.25,141.97, 141.81, 141.65, 138.36, 136.61, 136.35, 131.15, 131.13, 130.87,130.56, 129.68, 128.32, 127.85, 127.68, 127.23, 127.19, 125.72, 123.60,122.05, 121.22, 67.47, 56.19, 51.87, 21.36; HRMS (ESI-TOF) m/z Calcd forC₂₉H₂₇N₂O₄ [M+H]⁺: 467.1965, found: 467.1965.

Directing Group

Methyl3′-((tert-butoxycarbonyl)((3-methylpyridin-2-yl)-methyl)amino)-5′-methyl-[1,1′-biphenyl]-2-carboxylate(S6c)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J=4.4 Hz, 1H), 7.74(d, J=7.7 Hz, 1H), 7.47 (t, J=7.1 Hz, 1H), 7.42-7.33 (m, 2H), 7.30 (d,J=7.6 Hz, 1H), 7.12 (s, 1H), 7.10-7.03 (m, 2H), 6.89 (s, 1H), 4.93 (s,2H), 3.57 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.36 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 169.26, 155.35, 154.68, 146.58, 142.78, 141.97,141.19, 137.69, 137.45, 131.02, 130.93, 130.56, 129.53, 126.98, 126.33,125.88, 123.55, 121.90, 80.12, 53.50, 51.81, 28.18, 21.34, 18.03; HRMS(ESI-TOF) m/z Calcd for C₂₇H₃₁N₂O₄ [M+H]⁺: 447.2278, found: 447.2278.

Methyl3′-((tert-butoxycarbonyl)((3-methoxy-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)amino)-5′-methyl-[1,1′-biphenyl]-2-carboxylate(S6d)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.34 (d, J=5.6 Hz, 1H), 7.75(d, J=7.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.3 Hz, 1H), 7.30(d, J=7.5 Hz, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 6.89 (s, 1H), 6.60 (d,J=5.6 Hz, 1H), 4.94 (s, 2H), 4.37 (q, J=7.9 Hz, 2H), 3.59 (s, 3H), 2.32(s, 3H), 2.20 (s, 3H), 1.37 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 169.22,161.11, 157.10, 154.67, 147.78, 142.73, 141.97, 141.18, 137.70, 131.04,130.91, 130.55, 129.55, 127.00, 126.34, 125.83, 123.49, 122.99 (q,J=277.9 Hz), 119.77, 105.10, 80.19, 65.33 (q, J=36.3 Hz), 53.41, 51.81,28.19, 21.34, 9.64; ¹⁹F NMR (376 MHz, CDCl₃) δ −74.20; HRMS (ESI-TOF)m/z Calcd for C₂₉H₃₂F₃N₂O₆ [M+H]⁺: 545.2258, found: 545.2258.

Methyl3′-((tert-butoxycarbonyl)((3,4-dimethoxypyridin-2-yl)methyl)amino)-5′-methyl-[1,1′-biphenyl]-2-carboxylate(S6e)

Colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=5.5 Hz, 1H), 7.74(d, J=7.5 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.40-7.28 (m, 2H), 7.14 (s,1H), 7.11 (s, 1H), 6.89 (s, 1H), 6.75 (d, J=5.5 Hz, 1H), 4.98 (s, 2H),3.89 (s, 3H), 3.80 (s, 3H), 3.58 (s, 3H), 2.32 (s, 3H), 1.37 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 169.31, 157.99, 154.82, 151.39, 145.57,143.14, 142.81, 141.99, 141.15, 137.65, 131.01, 131.00, 130.94, 130.58,129.52, 126.94, 126.21, 125.89, 123.52, 106.51, 80.00, 60.40, 55.55,51.84, 50.86, 28.22, 21.35; HRMS (ESI-TOF) m/z Calcd for C₂₈H₃₃N₂O₆[M+H]⁺: 493.2333, found: 493.2332.

Meta-Arylation of Anilines

General Procedure for Meta-Arylation of Anilines:

Substrate 1 (0.1 mmol), Ar—I (0.2 mmol), Pd(OAc)₂ (2.2 mg, 10 mol %),L12 (3.0 mg, 20 mol %), AgOAc (50.1 mg, 0.3 mmol), 2-Norbornene (14.1mg, 0.15 mmol) or NBE-CO₂Me (21.6 mg, 0.15 mmol) and DCE (0.5 mL) wereadded to a 2 dram vial. The vial was capped and closed tightly. Then thereaction mixture was then stirred at 100° C. for 24 hours. After coolingto room temperature, the mixture was passed through a pad of Celite®with DCM as the eluent to remove the insoluble precipitate. The resultedsolution was concentrated and purified by preparative TLC to afford thedesired arylated product. (In cases where mono:di ratios are possible,the selectivity was determined by ¹H NMR.)

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-methyl-[1,1′-biphenyl]-2-carboxylate(5a)

Substrate 1a was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5a was obtained in 98% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.74 (d, J=7.6 Hz, 1H),7.47 (t, J=7.4 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.27 (d, J=9.1 Hz, 1H),7.09 (s, 1H), 7.02 (s, 1H), 6.87 (s, 1H), 4.90 (s, 2H), 3.71 (s, 3H),3.57 (s, 3H), 2.31 (s, 3H), 2.21 (s, 6H), 1.38 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 169.24, 163.59, 155.18, 154.67, 148.91, 142.61, 141.97,141.13, 137.63, 131.00, 130.92, 130.54, 129.52, 126.97, 126.33, 125.93,124.54, 123.64, 123.57, 80.09, 59.79, 53.54, 51.77, 28.22, 21.33, 13.16,10.38; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₅N₂O₅ [M+H]⁺: 491.2540, found:491.2540.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-methoxy-[1,1′-biphenyl]-2-carboxylate(5b)

Substrate 1b was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5b was obtained in 97% yield as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.75 (dd, J=7.7, 1.5 Hz,1H), 7.48 (td, J=7.5, 1.5 Hz, 1H), 7.37 (td, J=7.6, 1.4 Hz, 1H), 7.30(d, J=7.4 Hz, 1H), 6.86 (s, 1H), 6.83 (s, 1H), 6.62 (t, J=1.9 Hz, 1H),4.91 (s, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.59 (s, 3H), 2.21 (s, 3H),2.20 (s, 3H), 1.40 (s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 169.10, 163.62,159.09, 155.01, 154.56, 148.91, 143.74, 142.09, 141.80, 131.00, 130.45,129.49, 127.15, 124.58, 123.60, 119.21, 111.54, 111.26, 80.23, 59.79,55.31, 53.46, 51.85, 28.23, 13.14, 10.36; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₅N₂O₆ [M+H]⁺: 507.2490, found: 507.2490.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-(methylthio)-[1,1′-biphenyl]-2-carboxylate(5c)

Substrate 1c was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5c was obtained in 73% yield as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.77 (d, J=7.7 Hz, 1H),7.49 (t, J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H),7.18 (s, 1H), 7.03 (s, 1H), 6.95 (s, 1H), 4.90 (s, 2H), 3.72 (s, 3H),3.59 (s, 3H), 2.42 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.39 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 168.98, 163.62, 154.91, 154.50, 148.96,143.14, 141.75, 141.41, 137.98, 131.14, 130.87, 130.50, 129.66, 127.31,124.65, 123.64, 123.53, 80.36, 59.83, 53.37, 51.88, 28.23, 15.90, 13.17,10.38; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₅N₂O₅S [M+H]⁺: 523.2261, found:523.2261.

Methyl3′-(benzyl(tert-butoxycarbonyl)amino)-5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl)amino)-[1,1′-biphenyl]-2-carboxylate(5d)

Substrate 1d was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5d was obtained in 89% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.75 (d, J=7.7 Hz, 1H),7.46 (t, J=7.4 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.30-7.15 (m, 6H), 7.11(s, 1H), 7.05 (s, 1H), 6.89 (s, 1H), 4.84 (s, 2H), 4.78 (s, 2H), 3.70(s, 3H), 3.49 (s, 3H), 2.19 (s, 3H), 2.16 (s, 3H), 1.37 (s, 9H), 1.36(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.82, 163.59, 154.82, 154.49,154.47, 148.94, 142.97, 142.38, 141.48, 141.42, 138.51, 131.07, 130.84,130.55, 129.65, 128.26, 127.27, 127.20, 126.91, 124.55, 124.08, 123.91,123.46, 123.16, 80.41, 80.26, 59.80, 53.94, 53.38, 51.75, 28.21, 28.18,13.15, 10.32; HRMS (ESI-TOF) m/z Calcd for C₄₀H₄₈N₃O₇ [M+H]⁺: 682.3487,found: 682.3486.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-fluoro-[1,1′-biphenyl]-2-carboxylate(5e)

Substrate 1e was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5e was obtained in 94% yield as a colorlesssolid. mp=97° C., ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.80 (dd,J=7.7, 1.4 Hz, 1H), 7.50 (td, J=7.6, 1.5 Hz, 1H), 7.40 (td, J=7.6, 1.3Hz, 1H), 7.29 (dd, J=7.7, 1.4 Hz, 1H), 7.11-7.00 (m, 2H), 6.83-6.75 (m,1H), 4.89 (s, 2H), 3.73 (s, 3H), 3.62 (s, 3H), 2.22 (s, 3H), 2.20 (s,3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.59, 163.64, 161.86 (d,J=244.6 Hz), 154.63, 154.28, 149.03, 144.18 (d, J=10.2 Hz), 142.71 (d,J=9.7 Hz), 140.98 (d, J=1.8 Hz), 131.28, 130.65, 130.50, 129.83, 127.56,124.72, 123.39, 122.00, 112.39 (d, J=22.4 Hz), 80.65, 59.84, 53.29,51.92, 28.17, 13.18, 10.32; ¹⁹F NMR (376 MHz, CDCl₃) δ −114.11; HRMS(ESI-TOF) m/z Calcd for C₂₈H₃₂FN₂O₅ [M+H]⁺: 495.2290, found: 495.2289.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-chloro-[1,1′-biphenyl]-2-carboxylate(5f)

Substrate 1f was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5f was obtained in 92% yield as a colorlesssolid. mp=98° C., ¹H NMR (400 MHz, CDCl₃) δ 8.21 (s, 1H), 7.82 (d, J=7.7Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.36-7.28 (m,2H), 7.18 (s, 1H), 7.05 (s, 1H), 5.01 (s, 2H), 3.78 (s, 3H), 3.63 (s,3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 168.38, 165.08, 154.14, 153.64, 147.26, 143.18, 142.84, 140.70,133.18, 131.43, 130.64, 130.42, 129.95, 127.68, 125.79, 125.55, 125.31,124.82, 81.08, 60.11, 52.20, 51.92, 28.16, 28.13, 13.43, 10.58; HRMS(ESI-TOF) m/z Calcd for C₂₈H₃₂ClN₂O₅ [M+H]⁺: 511.1994, found: 511.1994.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylate(5g)

Substrate 1g was arylated following the general meta-arylation procedureusing NBE-CO₂Me. After purification by preparative thin-layerchromatography, Compound 5g was obtained in 94% yield as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.85 (d, J=7.6 Hz, 1H),7.57 (s, 1H), 7.53 (t, J=7.3 Hz, 1H), 7.48 (s, 1H), 7.43 (t, J=7.5 Hz,1H), 7.35-7.28 (m, 2H), 4.93 (s, 2H), 3.72 (s, 3H), 3.59 (s, 3H), 2.21(s, 6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.40, 163.70,154.52, 154.22, 149.07, 143.32, 142.18, 140.70, 131.48, 130.63, 130.57,130.18 (q, J=32.5 Hz), 130.12, 129.39, 127.81, 124.82, 123.85 (q,J=272.8 Hz), 123.47, 122.18, 122.07 (q, J=3.8 Hz), 80.87, 59.84, 53.13,51.85, 28.15, 13.18, 10.36; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.70; HRMS(ESI-TOF) m/z Calcd for C₂₉H₃₂F₃N₂O₅ [M+H]⁺: 545.2258, found: 545.2259.

Dimethyl5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-[1,1′-biphenyl]-2,3′-dicarboxylate(5h)

Substrate 1h was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5h was obtained in 94% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.95 (s, 1H), 7.84 (d,J=7.6 Hz, 1H), 7.75 (s, 1H), 7.56-7.45 (m, 2H), 7.41 (t, J=7.6 Hz, 1H),7.30 (d, J=7.6 Hz, 1H), 4.93 (s, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 3.58(s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.39 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 168.41, 166.57, 163.67, 154.70, 154.38, 149.00, 142.92, 141.68,141.21, 131.37, 130.99, 130.71, 130.43, 130.01, 127.54, 126.56, 126.36,124.71, 123.54, 80.60, 59.81, 53.18, 52.10, 51.83, 28.16, 13.16, 10.38;HRMS (ESI-TOF) m/z Calcd for C₃₀H₃₅N₂O₇ [M+H]⁺: 535.2439, found:535.2439.

Methyl3′-benzoyl-5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-[1,1′-biphenyl]-2-carboxylate(5i)

Substrate 1i was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5i was obtained in 93% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.84 (d, J=7.7 Hz, 1H),7.80 (s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.61-7.37 (m, 7H), 7.33 (d,J=7.6 Hz, 1H), 4.95 (s, 2H), 3.71 (s, 3H), 3.63 (s, 3H), 2.21 (s, 6H),1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 195.85, 168.29, 163.68, 154.67,154.43, 148.98, 142.87, 141.50, 141.26, 137.35, 137.33, 132.36, 131.42,130.82, 130.48, 130.41, 130.05, 130.02, 128.18, 127.56, 127.13, 126.67,124.71, 123.52, 80.63, 59.83, 53.20, 51.89, 28.19, 13.18, 10.37; HRMS(ESI-TOF) m/z Calcd for C₃₅H₃₇N₂O₆ [M+H]⁺: 581.2646, found: 581.2646.

Methyl 3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-cyano-[1,1′-biphenyl]-2-carboxylate(5j)

Substrate 1j was arylated following the general meta-arylation procedureusing NBE-CO₂Me. After purification by preparative thin-layerchromatography, Compound 5j was obtained in 93% yield as a colorlesssolid. mp=106° C., ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.89 (d,J=7.7 Hz, 1H), 7.62 (s, 1H), 7.60-7.50 (m, 2H), 7.45 (t, J=7.6 Hz, 1H),7.33 (s, 1H), 7.28 (d, J=9.0 Hz, 1H), 4.88 (s, 2H), 3.75 (s, 3H), 3.65(s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.38 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 167.80, 163.70, 154.19, 154.05, 149.12, 143.79, 142.73, 140.27,131.68, 130.88, 130.67, 130.31, 130.10, 128.52, 128.08, 124.90, 123.22,118.55, 111.81, 81.11, 59.88, 53.00, 51.99, 28.10, 13.20, 10.28; HRMS(ESI-TOF) m/z Calcd for C₂₉H₃₂N₃O₅ [M+H]⁺: 502.2336, found: 502.2336.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-nitro-[1,1′-biphenyl]-2-carboxylate(5k)

Substrate 1k was arylated following the general meta-arylation procedureusing NBE-CO₂Me. After purification by preparative thin-layerchromatography, Compound 5k was obtained in 89% yield as a light yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (q, J=2.1 Hz, 1H), 8.18 (s, 1H),7.96-7.88 (m, 2H), 7.67 (s, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.46 (t, J=7.5Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 4.93 (s, 2H), 3.75 (s, 3H), 3.65 (s,3H), 2.23 (s, 6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 167.74,163.75, 154.21, 154.02, 149.15, 147.71, 143.89, 142.56, 140.27, 132.22,131.76, 130.75, 130.40, 130.08, 128.19, 124.93, 123.33, 119.80, 81.27,59.90, 52.96, 52.02, 28.11, 13.22, 10.34; HRMS (ESI-TOF) m/z Calcd forC₂₈H₃₂N₃O₇ [M+H]⁺: 522.2235, found: 522.2235.

Dimethyl 5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(51)

Substrate 11 was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di<20:1). Afterpurification by preparative thin-layer chromatography, Compound 51 wasobtained in 92% yield as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃)δ 8.18 (s, 1H), 7.78 (dd, J=7.7, 1.4 Hz, 2H), 7.49 (td, J=7.5, 1.5 Hz,2H), 7.38 (td, J=7.6, 1.3 Hz, 2H), 7.34 (s, 1H), 7.32 (s, 1H), 7.29-7.21(m, 2H), 7.01 (t, J=1.7 Hz, 1H), 4.93 (s, 2H), 3.70 (s, 3H), 3.61 (s,6H), 2.21 (s, 6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.99,163.58, 155.04, 154.55, 148.94, 142.56, 141.68, 141.13, 131.09, 130.93,130.64, 129.68, 127.17, 125.60, 125.36, 124.58, 123.52, 80.18, 59.79,53.50, 51.84, 28.21, 13.15, 10.37; HRMS (ESI-TOF) m/z Calcd forC₃₆H₃₉N₂O₇ [M+H]⁺: 611.2752, found: 611.2754.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4′-methyl-[1,1′-biphenyl]-2-carboxylate(5m)

Substrate 1m was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5m was obtained in 81% yield as a colorlessliquid. Rotameric mixture, ratio of the rotamers=70/30; H NMR (400 MHz,CDCl₃) δ 8.11 (s, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.44 (t, J=7.5 Hz, 1H),7.34 (t, J=7.6 Hz, 1H), 7.31-6.98 (m, 3.3H), 6.86 (s, 0.7H), 5.26 (d,J=14.9 Hz, 0.7H), 5.18-5.04 (m, 0.3H), 4.51 (d, J=14.7 Hz, 1H), 3.66 (s,3H), 3.55 (s, 3H), 2.33-2.12 (m, 9H), 1.38 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) rotameric mixture, resonances for the minor rotamer are enclosedin parenthesis ( ): δ 169.20 (169.50), 163.76 (163.54), 155.07 (155.34),154.75 (154.09), 148.88, 141.49 (141.25), 140.41, 139.11, 134.90(135.29), 130.95, 130.86, 130.47, 130.27, 129.89, 129.59, 128.31,126.87, 124.95 (124.65), 123.71, 79.77 (79.90), 59.69, 52.52 (53.54),51.72 (51.84), 28.22, 17.31 (17.52), 13.13, 10.61; HRMS (ESI-TOF) m/zCalcd for C₂₉H₃₅N₂O₅ [M+H]⁺: 491.2540, found: 491.2540.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4′-methoxy-[1,1′-biphenyl]-2-carboxylate(5n)

Substrate 1n was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5n was obtained in 84% yield as a colorlessliquid. Rotameric mixture, ratio of the rotamers=75/25; ¹H NMR (400 MHz,CDCl₃) δ 8.07 (s, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H),7.32 (t, J=7.5 Hz, 1H), 7.26-6.76 (m, 4H), 5.33 (s, 0.75H), 4.91-4.30(m, 1.25H), 3.83 (s, 3H), 3.67 (s, 3H), 3.55 (s, 3H), 2.26 (s, 3H), 2.19(s, 3H), 1.49-1.30 (m, 9H); ¹³C NMR (150 MHz, CDCl₃) rotameric mixture:δ 169.56, 169.35, 163.76, 163.59, 155.70, 155.53, 155.24, 154.82,154.49, 148.62, 141.28, 133.15, 132.99, 130.88, 130.85, 130.63, 130.45,130.38, 129.53, 127.78, 127.71, 126.68, 126.62, 125.28, 124.84, 124.56,124.19, 111.22, 110.42, 79.98, 79.51, 59.70, 55.72, 55.31, 53.50, 52.50,51.86, 51.70, 28.19, 13.11, 10.58; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₅N₂O₆ [M+H]⁺: 507.2490, found: 507.2491.

Methyl 3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4′-fluoro-[1,1′-biphenyl]-2-carboxylate(5o)

Substrate 1o was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5o was obtained in 90% yield as a colorlessliquid. Rotameric mixture, ratio of the rotamers=75/25; ¹H NMR (400 MHz,CDCl₃) δ 8.10 (s, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.47 (td, J=7.5,1.5 Hz, 1H), 7.37 (t, J=7.3 Hz, 1H), 7.25-6.91 (m, 4H), 4.94 (s, 2H),3.70 (s, 3H), 3.56 (s, 3H), 2.26 (s, 3H), 2.19 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 168.85, 163.77, 157.50 (d, J=249.6 Hz),154.68, 154.23, 148.77, 140.84, 137.07 (d, J=3.7 Hz), 131.16, 130.73,130.55, 129.80, 129.50, 129.36, 129.28, 127.78 (d, J=7.8 Hz), 127.24,124.96, 115.06 (d, J=21.6 Hz), 80.50, 59.74, 52.70, 51.74, 28.07, 13.14,10.48; ¹⁹F NMR (376 MHz, CDCl₃) for major isomer: δ −123.17; ¹⁹F NMR(376 MHz, CDCl₃) for minor isomer: δ −122.57; HRMS (ESI-TOF) m/z Calcdfor C₂₈H₃₂FN₂O₅ [M+H]⁺: 495.2290, found: 495.2291.

Dimethyl5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-2′-fluoro-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(5p)

Substrate 1p was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of the crude reaction mixture by ¹H NMRshowed the selectivity of mono- and di-products (mono:di<20:1). Afterpurification by preparative thin-layer chromatography, Compound 5p wasobtained in 90% yield as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.17 (s, 1H), 7.91 (d, J=7.7 Hz, 2H), 7.53 (t, J=7.5 Hz, 2H), 7.41 (t,J=7.6 Hz, 2H), 7.29 (d, J=7.7 Hz, 2H), 7.18 (s, 2H), 4.95 (s, 2H), 3.70(s, 3H), 3.64 (s, 6H), 2.21 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 167.79, 163.69, 154.99, 154.58, 153.56 (d, J=244.3 Hz), 148.91,138.04, 136.02, 131.52, 131.42, 130.96, 130.01, 128.54 (d, J=18.4 Hz),127.98, 127.80, 124.74, 123.92, 80.29, 59.78, 53.54, 51.87, 28.24,13.16, 10.44; ¹⁹F NMR (376 MHz, CDCl₃) δ −123.88; HRMS (ESI-TOF) m/zCalcd for C₃₆H₃₈FN₂O₇ [M+H]⁺: 629.2658, found: 629.2657.

Methyl5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-2′-methoxy-[1,1′-biphenyl]-2-carboxylate(5q)

Substrate 1q was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di>20:1). Afterpurification by preparative thin-layer chromatography, Compound 5q wasobtained in 64% yield as a colorless liquid. ¹H NMR (400 MHz, CDCl₃) δ8.14 (s, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.37 (t,J=7.6 Hz, 1H), 7.16 (brs, 2H), 7.01 (s, 1H), 6.73 (d, J=8.7 Hz, 1H),4.93 (brs, 2H), 3.70 (s, 3H), 3.65 (s, 3H), 3.56 (s, 3H), 2.30-2.10 (m,6H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.60, 163.75, 155.29,154.99, 153.89, 148.84, 138.17, 135.35, 131.60, 131.49, 131.20, 130.30,129.32, 128.85, 127.12, 126.88, 124.74, 124.39, 109.71, 80.03, 59.79,55.35, 53.66, 51.48, 28.30, 13.17, 10.51; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₅N₂O₆ [M+H]⁺: 507.2490, found: 507.2491.

Methyl2-(6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)benzo[d][1,3]dioxol-4-yl)benzoate(5r)

Substrate 1r was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5r was obtained in 83% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.86 (d, J=7.7 Hz, 1H),7.51 (t, J=7.5 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H),6.81 (s, 1H), 6.68 (s, 1H), 5.87 (s, 2H), 4.88 (s, 2H), 3.71 (s, 3H),3.67 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 168.36, 163.70, 155.02, 154.92, 148.85, 146.61, 142.64,136.74, 135.93, 131.57, 130.88, 130.76, 130.06, 127.66, 124.71, 123.99,121.88, 120.87, 107.96, 101.15, 80.15, 59.79, 53.76, 51.89, 28.24,13.16, 10.41; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₃N₂O₇ [M+H]⁺: 521.2282,found: 521.2283.

Methyl5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-2′-fluoro-3′-methyl-[1,1′-biphenyl]-2-carboxylate(5s)

Substrate 1s was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5s was obtained in 94% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.92 (d, J=7.7 Hz, 1H),7.52 (td, J=7.6, 1.4 Hz, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.23 (d, J=7.6 Hz,1H), 7.10 (s, 1H), 6.96 (s, 1H), 4.90 (s, 2H), 3.71 (s, 3H), 3.63 (s,3H), 2.21 (d, J=2.3 Hz, 9H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ167.87, 163.69, 155.58 (d, J=243.2 Hz), 155.03, 154.69, 148.85, 137.86,136.35, 131.58, 131.32, 130.77, 129.96, 128.67 (d, J=5.1 Hz), 128.35 (d,J=18.1 Hz), 127.66, 126.39, 124.71, 124.08 (d, J=19.5 Hz), 123.89,80.20, 59.78, 53.57, 51.74, 28.22, 14.66 (d, J=4.0 Hz), 13.15, 10.41;¹⁹F NMR (376 MHz, CDCl₃) δ −124.82; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₄FN₂O₅ [M+H]⁺: 509.2446, found: 509.2447.

Methyl5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4′-fluoro-2′-methoxy-[1,1′-biphenyl]-2-carboxylate(5t)

Substrate 1t was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5t was obtained in 92% yield as a colorlesssolid. Rotameric mixture, ratio of the rotamers=76/24; ¹H NMR (400 MHz,CDCl₃) δ 8.09 (s, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H),7.36 (t, J=7.6 Hz, 1H), 7.14 (s, 0.48H), 6.99 (s, 0.76H), 6.83 (s,0.76H), 6.54 (d, J=11.7 Hz, 1H), 5.30-4.60 (m, 2H), 3.68 (s, 3H), 3.64(s, 3H), 3.56 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H), 1.41 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) rotameric mixture: δ 168.42, 163.89, 163.80, 158.89,157.23, 155.41, 155.35, 155.02, 154.66, 154.29, 148.71, 137.20, 131.49,131.12, 130.76, 130.71, 130.56, 129.44, 127.23, 125.97, 125.40, 125.07,124.87, 124.36, 121.96, 121.54, 121.46, 99.03, 98.88, 98.52, 98.35,80.59, 59.71, 55.55, 53.83, 52.66, 51.41, 28.12, 13.14, 10.57; ¹⁹F NMR(376 MHz, CDCl₃) for major isomer: δ −119.67; ¹⁹F NMR (376 MHz, CDCl₃)for minor isomer: δ −118.80; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₄FN₂O₆[M+H]⁺: 525.2395, found: 525.2395.

Dimethyl5′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4′-methyl-[1,1′-biphenyl]-2,3′-dicarboxylate(5u)

Substrate 1u was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5u was obtained in 92% yield as a colorlessliquid. Rotameric mixture, ratio of the rotamers=74/26; ¹H NMR (400 MHz,CDCl₃) δ 8.22-8.05 (m, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.70 (s, 0.74H),7.59 (d, J=3.7 Hz, 0.26H), 7.47 (t, J=7.5 Hz, 1H), 7.38 (t, J=7.6 Hz,1H), 7.34-7.04 (m, 2H), 5.35-5.05 (m, 1H), 4.54-4.30 (m, 1H), 3.87 (s,3H), 3.67 (s, 3H), 3.55 (s, 3H), 2.57-2.38 (m, 3H), 2.27-2.15 (m, 6H),1.37 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) rotameric mixture: δ 169.05,168.64, 167.81, 163.78, 163.55, 155.01, 154.64, 154.30, 148.94, 142.67,141.82, 140.66, 138.61, 137.22, 136.92, 132.94, 132.41, 131.20, 130.57,130.50, 129.93, 129.13, 127.38, 124.99, 124.77, 124.67, 123.49, 80.13,59.70, 53.43, 52.55, 51.92, 51.75, 28.17, 15.00, 13.12, 10.61; HRMS(ESI-TOF) m/z Calcd for C₃₁H₃₇N₂O₇ [M+H]⁺: 549.2595, found: 549.2596.

Methyl 2-(4-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)naphthalen-2-yl)benzoate (5v)

Substrate 1v was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 5v was obtained in 92% yield as a colorlesssolid. Rotameric mixture, ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.92(s, 1H), 7.87-7.77 (m, 2H), 7.66 (s, 1H), 7.56-7.44 (m, 3H), 7.40 (t,J=7.5 Hz, 1H), 7.34-7.18 (m, 2H), 5.56-5.18 (m, 1H), 4.61 (d, J=15.2 Hz,1H), 3.63 (s, 3H), 3.46 (s, 3H), 2.18 (s, 3H), 2.16 (s, 3H), 1.56-1.14(m, 9H); ¹³C NMR (150 MHz, CDCl₃) rotameric mixture: δ 169.07, 163.64,155.33, 155.03, 148.96, 141.59, 138.49, 138.37, 134.01, 131.13, 131.01,130.80, 129.82, 128.36, 127.66, 127.20, 126.76, 126.17, 126.07, 124.76,124.46, 123.31, 122.91, 79.96, 59.67, 53.15, 51.75, 50.06, 28.07, 13.10,10.52; HRMS (ESI-TOF) m/z Calcd for C₃₂H₃₅N₂O₅ [M+H]⁺: 527.2540, found:527.2541.

Methyl2-(3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)naphthalene-1-yl)benzoate(5w)

Substrate 1w was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography Compound 5w was obtained in 92% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 8.00 (d, J=7.8 Hz, 1H),7.74 (d, J=8.1 Hz, 1H), 7.66 (s, 1H), 7.58 (t, J=7.3 Hz, 1H), 7.49 (t,J=7.6 Hz, 1H), 7.41-7.22 (m, 5H), 5.06 (s, 2H), 3.70 (s, 3H), 3.23 (s,3H), 2.24 (s, 3H), 2.20 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 167.79, 163.68, 155.11, 154.65, 148.94, 140.85, 139.61, 139.57,133.26, 131.79, 131.61, 131.43, 130.13, 130.00, 128.09, 127.57, 126.09,125.60, 125.52, 125.10, 124.67, 123.85, 122.79, 80.40, 59.81, 53.70,51.56, 28.27, 13.17, 10.48; HRMS (ESI-TOF) m/z Calcd for C₃₂H₃₅N₂O₅[M+H]⁺: 527.2540, found: 527.2538.

Meta-Arylation of Heterocycle-Containing Aromatic Amines

General Procedures for Meta-Arylation of Heterocycle-Containing AromaticAmines:

Substrate 2 (0.1 mmol), Ar—I (0.2 mmol), Pd(OAc)₂ (2.2 mg, 10 mol %),L12 (3.0 mg, 20 mol %), AgOAc (50.1 mg, 0.3 mmol), 2-Norbornene (14.1mg, 0.15 mmol) or NEE-CO₂Me (21.6 mg, 0.15 mmol) and DCE (0.5 mL) wereadded to a 2-dram vial. The vial was capped and closed tightly. Then thereaction mixture was then stirred at 100° C. for 24 hours. After coolingto room temperature, the mixture was passed through a pad of Celite®with DCM as the eluent to remove the insoluble precipitate. Theresultant solution was concentrated and purified by preparative TLCplate to afford the desired arylated product.

Methyl2-(5-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-6-chloropyridin-3-yl)benzoate(6a)

Substrate 2a was arylated following the general meta-arylation procedureusing NBE-CO₂Me. After purification by preparative thin-layerchromatography, Compound 6a was obtained in 53% yield as a colorlessliquid. Rotameric mixture, ratio of the rotamers=77/23; ¹H NMR (400 MHz,CDCl₃) δ 8.25-8.12 (m, 1H), 8.10 (s, 0.77H), 7.99 (s, 0.23H), 7.92 (d,J=7.7 Hz, 1H), 7.65 (s, 0.77H), 7.55 (t, J=7.4 Hz, 1H), 7.47 (t, J=7.6Hz, 1H), 7.27 (s, 0.46H), 7.17 (d, J=7.6 Hz, 0.77H), 5.24 (d, J=15.5 Hz,1H), 4.56 (d, J=15.5 Hz, 1H), 3.71 (s, 3H), 3.60 (s, 3H), 2.33-2.23 (m,3H), 2.20 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) rotamericmixture: δ 167.98, 167.68, 163.94, 163.69, 154.64, 154.12, 153.79,149.03, 148.91, 148.78, 146.47, 140.22, 138.99, 137.15, 136.54, 136.33,135.68, 131.78, 130.84, 130.60, 130.46, 130.29, 128.36, 128.26, 125.26,124.97, 124.86, 123.59, 81.08, 59.79, 52.51, 51.91, 51.67, 28.09, 13.18,10.67, 10.50; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₁ClN₃O₅ [M+H]⁺:512.1947, found: 512.1946.

Methyl2-(2-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-6-methoxypyridin-4-yl)benzoate(6b)

Substrate 2b was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6b was obtained in 72% yield as a colorlessliquid. Only 4% NMR yield was obtained in the absence of L12. ¹H NMR(400 MHz, CDCl₃) δ 8.13 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.51 (t, J=7.5Hz, 1H), 7.46-7.39 (m, 2H), 7.36 (d, J=7.5 Hz, 1H), 6.32 (s, 1H), 5.24(s, 2H), 3.73 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H), 2.26 (s, 3H), 2.21(s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.27, 163.33,161.85, 156.03, 154.28, 153.00, 151.84, 148.82, 140.63, 131.35, 130.42,130.26, 129.83, 127.90, 123.82, 122.36, 110.87, 104.23, 80.92, 59.83,53.00, 52.05, 49.35, 28.13, 13.14, 10.34; HRMS (ESI-TOF) m/z Calcd forC₂₈H₃₄N₃O₆ [M+H]⁺: 508.2442, found: 508.2442.

Methyl 2-(5-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-thiophen-3-yl)benzoate(6c)

Substrate 2c was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6c was obtained in 79% yield as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 7.71 (d, J=7.7 Hz, 1H),7.56-7.39 (m, 2H), 7.34 (t, J=7.4 Hz, 1H), 6.97 (s, 1H), 6.80 (s, 1H),5.48 (s, 2H), 3.96 (s, 3H), 3.73 (s, 3H), 2.35 (s, 6H), 1.50 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 169.58, 168.72, 153.40, 150.44, 141.74,138.94, 136.46, 131.35, 130.71, 130.40, 129.44, 128.83, 128.72, 128.13,127.24, 123.99, 118.73, 82.96, 60.92, 52.06, 49.86, 28.09, 14.16, 11.10;HRMS (ESI-TOF) m/z Calcd for C₂₆H₃₁N₂O₅S [M+H]⁺: 483.1948, found:483.1949.

Methyl2-(4-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-thiophen-2-yl)benzoate(6d)

Substrate 2d was arylated following the general meta-arylation procedureusing NBE-CO₂Me. After purification by preparative thin-layerchromatography, Compound 6d was obtained in 56% yield as a colorlessliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.66 (d, J=7.6 Hz, 1H),7.49-7.39 (m, 2H), 7.39-7.32 (m, 1H), 7.07 (s, 1H), 6.96 (s, 1H), 4.91(s, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 2.26-2.19 (m, 6H), 1.44 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 169.04, 163.69, 154.77, 154.18, 149.05,140.87, 139.46, 134.13, 131.51, 130.88, 129.27, 127.64, 124.68, 123.50,115.39, 80.72, 59.86, 53.21, 52.13, 28.25, 13.20, 10.29; HRMS (ESI-TOF)m/z Calcd for C₂₆H₃₁N₂O₅S [M+H]⁺: 483.1948, found: 483.1948.

Methyl3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5-(2-(methoxycarbonyl)-phenyl)thiophene-2-carboxylate(6e)

Substrate 2e was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6e was obtained in 65% yield as a colorlessliquid. Rotameric mixture, ratio of the rotamers=65/35; ¹H NMR (400 MHz,CDCl₃) δ 8.13 (s, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.5 Hz, 1H),7.45-7.29 (m, 2H), 7.06 (s, 0.35H), 6.80 (s, 0.65H), 5.20-4.60 (m, 2H),3.85 (s, 3H), 3.72 (s, 3H), 3.66 (s, 3H), 2.26 (s, 3H), 2.20 (s, 3H),1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) rotameric mixture: δ 168.16,167.85, 163.31, 163.14, 161.03, 160.90, 154.89, 154.29, 153.70, 132.81,131.11, 131.03, 130.72, 130.38, 129.28, 128.41, 128.18, 128.10, 127.77,124.49, 124.38, 124.28, 124.12, 124.05, 123.05, 79.91, 59.37, 53.02,52.14, 51.79, 51.68, 51.47, 27.72, 12.74, 10.07; HRMS (ESI-TOF) m/zCalcd for C₂₈H₃₃N₂O₇S [M+H]⁺: 541.2003, found: 541.2003.

Methyl2-(5-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-quinolin-7-yl)benzoate(6f)

Substrate 2f was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6f was obtained in 76% yield as a red liquid.¹H NMR (400 MHz, CDCl₃) δ 8.91 (dd, J=4.2, 1.6 Hz, 1H), 8.34 (d, J=8.4Hz, 1H), 8.12 (s, 1H), 7.97 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.55 (t,J=7.3 Hz, 1H), 7.51-7.30 (m, 4H), 5.24 (d, J=15.5 Hz, 1H), 4.76 (d,J=15.3 Hz, 1H), 3.65 (s, 3H), 3.52 (s, 3H), 2.28-2.10 (m, 6H), 1.54-1.10(m, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.50, 163.67, 154.97, 154.56,150.52, 148.99, 148.57, 142.19, 141.25, 138.52, 132.00, 131.46, 130.91,130.66, 130.17, 127.65, 127.48, 126.97, 125.23, 124.87, 124.23, 120.86,80.44, 59.72, 53.40, 51.82, 28.08, 13.12, 10.51; HRMS (ESI-TOF) m/zCalcd for C₃₁H₃₄N₃O₅ [M+H]⁺: 528.2493, found: 528.2493.

Methyl2-(1-acetyl-6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-amino)-indolin-4-yl)-benzoate(6g)

Substrate 2g was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6g was obtained in 89% yield as a light yellowsolid. Rotameric mixture, ratio of the rotamers=78/22; mp=79° C., ¹H NMR(400 MHz, CDCl₃) δ 8.20-8.08 (m, 1.78H), 7.96-7.84 (m, 1H), 7.50 (t,J=7.6 Hz, 1H), 7.40 (t, J=7.6 Hz, 1H), 7.26-7.09 (m, 1.22H), 6.74 (s,1H), 5.00-4.80 (m, 2H), 4.12-3.90 (m, 2H), 3.70 (s, 2H), 3.66-3.52 (m,3H), 2.82 (t, J=8.4 Hz, 1.56H), 2.69 (t, J=8.4 Hz, 0.44H), 2.38-2.08 (m,9H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) resonances for the minorrotamer are enclosed in parenthesis ( ): δ 168.46 (168.29), 167.88(167.52), 163.60 (163.66), 155.15 (155.03), 154.68, 148.74 (148.82),142.41, 142.00 (141.16), 140.54 (140.45), 137.49 (138.91), 131.49(131.67), 130.52 (130.47), 130.13 (129.85), 129.97 (129.28), 127.41(127.61), 126.70, 124.50 (124.75), 123.90, 122.52 (121.91), 114.62(112.46), 80.12 (80.33), 59.74 (59.79), 53.54, 51.87 (51.92), 49.12(48.19), 28.21, 26.81 (25.60), 24.14 (24.36), 13.12, 10.45 (10.37); HRMS(ESI-TOF) m/z Calcd for C₃₂H₃₈N₃O₆ [M+H]⁺: 560.2755, found: 560.2755.

tert-Butyl6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4-(2-(methoxycarbonyl)-phenyl)-1H-indole-1-carboxylate(6h)

Substrate 2h was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6h was obtained in 66% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.99 (s, 1H), 7.89 (d,J=7.7 Hz, 1H), 7.57-7.47 (m, 2H), 7.43 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.5Hz, 1H), 7.03 (s, 1H), 6.22 (d, J=3.7 Hz, 1H), 5.01 (s, 2H), 3.71 (s,3H), 3.42 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 1.60 (s, 9H), 1.40 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.58, 163.70, 155.30, 154.94, 149.55,148.84, 140.23, 139.22, 134.48, 133.59, 131.39, 131.32, 131.14, 129.92,127.36, 127.32, 126.33, 124.64, 124.05, 122.40, 112.86, 105.68, 83.59,80.08, 59.76, 54.11, 51.88, 28.27, 28.04, 13.12, 10.50; HRMS (ESI-TOF)m/z Calcd for C₃₅H₄₂N₃O₇ [M+H]⁺: 616.3017, found: 616.3018.

tert-Butyl4-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-6-(2-(methoxycarbonyl)-phenyl)-1H-indole-1-carboxylate(6i)

Substrate 2i was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6i as obtained in 51% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.13 (s, 1H), 8.01 (s, 1H), 7.75 (d,J=7.7 Hz, 1H), 7.56 (d, J=3.7 Hz, 1H), 7.48 (t, J=7.4 Hz, 1H), 7.41-7.28(m, 2H), 7.02 (brs, 1H), 6.58 (d, J=3.7 Hz, 1H), 4.97 (brs, 2H), 3.66(s, 3H), 3.54 (s, 3H), 2.18 (s, 6H), 1.64 (s, 9H), 1.35 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 169.41, 163.58, 155.02, 154.78, 149.61, 148.93,142.31, 137.48, 135.73, 134.72, 131.18, 130.97, 130.92, 129.65, 127.71,126.83, 125.87, 124.67, 124.15, 121.93, 113.59, 105.71, 83.78, 80.07,59.72, 53.36, 51.76, 28.20, 28.13, 13.15, 10.50; HRMS (ESI-TOF) m/zCalcd for C₃₅H₄₂N₃O₇ [M+H]⁺: 616.3017, found: 616.3018.

Methyl2-(6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-methyl-1H-indazol-4-yl)benzoate(6j)

Substrate 2j was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6j as obtained in 90% yield as a colorlesssolid. mp=79° C., ¹H NMR (400 MHz, CDCl₃) δ 8.18 (s, 1H), 7.90 (d, J=7.7Hz, 1H), 7.63 (s, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H),7.39 (d, J=7.6 Hz, 1H), 7.35 (s, 1H), 6.98 (s, 1H), 5.00 (s, 2H), 4.00(s, 3H), 3.71 (s, 3H), 3.44 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.40(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.39, 163.70, 155.05, 154.71,148.89, 141.40, 139.77, 139.61, 134.29, 131.56, 131.45, 131.09, 131.02,130.00, 127.64, 124.73, 123.79, 121.46, 120.66, 105.64, 80.43, 59.80,53.89, 51.89, 35.65, 28.23, 13.17, 10.45; HRMS (ESI-TOF) m/z Calcd forC₃₀H₃₅N₄O₅ [M+H]⁺: 531.2602, found: 531.2604.

Methyl2-(6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4-oxo-2-phenyl-4H-chromen-8-yl)benzoate(6k)

Substrate 2k was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6k was obtained in 87% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 8.11 (d, J=7.7 Hz, 1H),8.01 (d, J=2.6 Hz, 1H), 7.78-7.62 (m, 2H), 7.61-7.49 (m, 3H), 7.48-7.33(m, 4H), 6.77 (s, 1H), 5.02 (q, J=15.1, 14.2 Hz, 2H), 3.74 (s, 3H), 3.40(s, 3H), 2.25 (s, 3H), 2.21 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 178.08, 167.21, 163.75, 162.67, 154.60, 154.40, 150.81, 149.03,139.91, 136.59, 134.50, 133.25, 132.19, 131.89, 131.69, 131.39, 131.27,130.74, 130.52, 130.27, 128.83, 128.39, 126.00, 124.81, 123.70, 123.49,120.74, 106.72, 80.78, 59.88, 53.26, 51.70, 28.20, 13.19, 10.44; HRMS(ESI-TOF) m/z Calcd for C₃₇H₃₇N₂O₇ [M+H]⁺: 621.2595, found: 621.2596.

Methyl2-(7-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)benzoate(6l)

Substrate 2l was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 6l was obtained in 91% yield as a colorlesssolid. ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.84 (d, J=7.7 Hz, 1H),7.50 (t, J=7.5 Hz, 1H), 7.36 (s, 1H), 7.21 (d, J=6.4 Hz, 1H), 6.81 (s,1H), 6.67 (s, 1H), 4.89 (s, 2H), 4.15 (dd, J=5.6, 2.8 Hz, 2H), 4.09 (dd,J=5.7, 2.8 Hz, 2H), 3.71 (s, 3H), 3.64 (s, 3H), 2.21 (s, 3H), 2.20 (s,3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 168.41, 163.63, 155.14,154.84, 148.86, 142.40, 138.20, 137.39, 135.73, 131.50, 131.39, 131.22,129.88, 129.41, 127.28, 124.60, 123.90, 120.95, 115.08, 80.03, 64.11,64.02, 59.77, 53.66, 51.62, 28.25, 13.14, 10.39; HRMS (ESI-TOF) m/zCalcd for C₃₀H₃₅N₂O₇ [M+H]⁺: 535.2439, found: 535.2438.

Meta-Arylation of Phenols

General Procedure for Meta-Arylation of Phenols:

Substrate 3 (0.2 mmol), Ar—I (0.6 mmol), Pd(OAc)₂ (4.5 mg, 10 mol %),L14 (4.4 mg, 10 mol %), AgOAc (100.0 mg, 0.6 mmol), NBE-CO₂Me (45.6 mg,0.3 mmol) and CHCl₃ (1.0 mL) were added to a 50 mL schlenk tube. Thetube was capped and closed tightly. The reaction mixture was thenstirred at 100° C. for 24 hours. After cooling to room temperature, themixture was passed through a pad of Celite® with EtOAc as the eluent toremove the insoluble precipitate. The resulting solution wasconcentrated and purified by preparative TLC plate to afford the desiredarylated product. (In cases where mono:di ratios are possible, theselectivity was determined by ¹H NMR.)

Methyl3′-methyl-5′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7a)

Substrate 3a was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7a was obtained in 87% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.4 Hz, 1H), 7.77 (d, J=7.5Hz, 1H), 7.54-7.45 (m, 1H), 7.41-7.34 (m, 2H), 7.19 (dd, J=7.7, 4.8 Hz,2H), 6.86 (s, 1H), 6.80 (s, 1H), 6.74 (s, 1H), 5.20 (s, 2H), 3.63 (s,3H), 2.43 (s, 3H), 2.36 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.26,158.48, 154.32, 146.55, 142.35, 142.13, 139.01, 138.34, 133.22, 131.04,131.02, 130.46, 129.49, 127.06, 123.38, 122.02, 114.56, 111.92, 70.81,51.92, 21.53, 18.16; HRMS (ESI-TOF) m/z Calcd for C₂₂H₂₂NO₃ [M+H]⁺:348.1594, found: 348.1598.

Methyl3′-methoxy-5′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7b)

Substrate 3b was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7b was obtained in 91% yield as a light yellowliquid ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.7 Hz, 1H), 7.76 (d, J=7.6Hz, 1H), 7.54-7.46 (m, 2H), 7.42-7.35 (m, 2H), 7.19 (dd, J=7.7, 4.8 Hz,1H), 6.26-6.58 (m, 2H), 6.48 (s, 1H), 5.19 (s, 2H), 3.79 (s, 3H), 3.64(s, 3H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.18, 160.32,159.56, 154.14, 146.61, 143.23, 142.00, 138.36, 133.17, 131.09, 131.05,130.34, 129.47, 127.24, 123.42, 107.40, 107.03, 100.18, 70.86, 55.33,51.99, 18.14; HRMS (ESI-TOF) m/z Calcd for C₂₂H₂₂NO₄ [M+H]⁺: 364.1543,found: 364.1552.

Methyl3′-(1,3-dioxolan-2-yl)-5′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7c)

Substrate 3c was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7c was obtained in 53% yield as a clear liquid.¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.8 Hz, 1H), 7.79 (d, J=7.6 Hz,1H), 7.55-7.46 (m, 2H), 7.43-7.34 (m, 2H), 7.19 (dd, J=7.7, 4.8 Hz, 1H),7.16 (s, 1H), 7.03 (s, 1H), 7.01 (t, J=1.9 Hz, 1H); 5.82 (s, 1H), 5.23(s, 2H), 4.16-3.95 (m, 4H), 3.61 (s, 3H), 2.43 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 169.21, 158.58, 154.15, 146.61, 142.68, 141.68, 139.35,138.39, 133.30, 131.15, 131.06, 130.54, 129.68, 127.31, 123.48, 119.50,115.78, 111.57, 103.46, 71.00, 65.27, 51.98, 18.20; HRMS (ESI-TOF) m/zCalcd for C₂₄H₂₄NO₅ [M+H]⁺: 406.1649, found: 406.1656.

Methyl 3′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7d)

Substrate 3d was arylated following the general meta-arylation procedurefor phenols. Analysis of crude reaction mixture by ¹H NMR showed theselectivity of mono- and di-products (mono:di=1:1). After purificationby preparative thin-layer chromatography, Compound 7d was obtained in38% yield as a clear liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.3Hz, 1H), 7.81-7.77 (m, 1H), 7.54-7.49 (m, 2H), 7.40 (td, J=7.6, 1.3 Hz,1H), 7.38-7.35 (m, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.19 (dd, J=7.7, 4.8 Hz,1H), 7.03 (ddd, J=8.3, 2.6, 0.9 Hz, 1H), 7.00 (s, 1H), 6.90 (ddd, J=7.5,1.7, 0.9 Hz, 1H), 5.22 (s, 2H), 3.62 (s, 3H), 2.44 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 169.15, 158.53, 154.28, 146.61, 142.68, 142.10, 138.40,133.27, 131.15, 130.99, 130.55, 129.64, 128.99, 127.20, 123.44, 121.24,114.99, 113.63, 70.89, 51.95, 18.20; HRMS (ESI-TOF) m/z Calcd forC₂₁H₂₀NO₃ [M+H]⁺: 334.1438, found: 334.1443.

Dimethyl5′-((3-methylpyridin-2-yl)methoxy)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(7d′)

Substrate 3d was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7d′ was obtained in 40% yield as a clearliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d, J=4.9 Hz, 1H), 7.81-7.76 (m,2H), 7.55-7.48 (m, 3H), 7.43-7.37 (m, 4H), 7.20 (dd, J=7.7, 4.8 Hz, 1H),6.99 (s, 2H), 6.86 (s, 1H), 5.23 (s, 2H), 3.65 (s, 6H), 2.44 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 169.09, 158.22, 154.11, 146.58, 142.40,141.86, 138.43, 133.25, 131.13, 131.05, 130.58, 129.67, 127.27, 123.47,121.51, 113.81, 70.88, 51.98, 18.19; HRMS (ESI-TOF) m/z Calcd forC₂₉H₂₆NO₅ [M+H]⁺: 468.1805, found: 468.1809.

Methyl4′-methyl-3′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7e)

Substrate 3e was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7e was obtained in 85% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.6 Hz, 1H), 7.78 (d, J=7.6Hz, 1H), 7.55-7.47 (m, 2H), 7.42-7.33 (m, 2H), 7.20 (dd, J=7.7, 4.8 Hz,1H), 7.15 (d, J=7.5 Hz, 1H), 7.01 (s, 1H), 6.82 (d, J=7.6 Hz, 1H), 5.21(s, 2H), 3.64 (d, J=0.7 Hz, 3H), 2.45 (s, 3H), 2.25 (s, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 169.32, 156.53, 154.54, 146.49, 142.29, 139.95,138.32, 133.39, 131.09, 131.00, 130.62, 130.27, 129.54, 126.94, 125.90,123.39, 120.64, 111.72, 71.19, 51.97, 18.16, 16.08; HRMS (ESI-TOF) m/zCalcd for C₂₂H₂₂NO₃ [M+H]⁺: 348.1594, found: 348.1597.

Methyl4′-isopropyl-3′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7f)

Substrate 3f was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7f was obtained in 89% yield as clear liquid.¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.6 Hz, 1H), 7.77 (d, J=7.2 Hz,1H), 7.56-7.46 (m, 2H), 7.42-7.35 (m, 2H), 7.26-7.16 (m, 2H), 7.04 (s,1H), 6.89 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.63 (s, 3H), 3.34 (hept,J=7.0 Hz, 1H), 2.45 (s, 3H), 1.20 (d, J=6.9 Hz, 6H); ¹³C NMR (100 MHz,CDCl₃) δ 169.43, 155.58, 154.58, 146.52, 142.18, 139.50, 138.28, 136.18,133.32, 131.09, 131.03, 130.59, 129.49, 126.90, 125.70, 123.39, 120.94,111.96, 71.28, 51.93, 26.36, 22.84, 18.14; HRMS (ESI-TOF) m/z Calcd forC₂₄H₂₆NO₃ [M+H]⁺: 376.1907, found: 376.1907.

Methyl4′-methoxy-3′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7g)

Substrate 3g was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7g was obtained in 54% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl3) δ 8.42 (d, J=4.9 Hz, 1H), 7.76 (d, J=7.7Hz, 1H), 7.53-7.47 (m, 2H), 7.37 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.7 Hz,1H), 7.17 (dd, J=7.7, 4.8 Hz, 1H), 7.07 (d, J=1.2 Hz, 1H), 6.94-6.84 (m,2H), 5.25 (s, 2H), 3.88 (s, 3H), 3.63 (s, 3H), 2.47 (s, 3H); ¹³C NMR(100 MHz, CDCl3) δ 169.39, 154.26, 149.19, 147.74, 146.49, 141.84,138.36, 133.85, 133.43, 131.08, 130.96, 130.63, 129.58, 126.81, 123.35,121.44, 114.84, 111.27, 72.02, 55.89, 51.96, 18.20; HRMS (ESI-TOF) m/zCalcd for C₂₂H₂₂NO₄[M+H]⁺: 364.1543, found: 364.1547.

Methyl4′-chloro-3′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7h)

Substrate 3h was arylated following a slightly modified meta-arylationprocedure for phenols. For this substrate, L12 was used in place of L14and the reaction was run for 36 hours. After purification by preparativethin-layer chromatography, Compound 7h was obtained in 81% yield as acolorless solid. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=4.7 Hz, 1H), 7.83(d, J=7.7 Hz, 1H), 7.56-7.49 (m, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.35 (d,J=8.1 Hz, 1H), 7.30 (d, J=7.7 Hz, 1H), 7.20 (dd, J=7.7, 4.8 Hz, 1H),7.14 (d, J=1.9 Hz, 1H), 6.82 (dd, J=8.1, 1.9 Hz, 1H), 5.29 (s, 2H), 3.62(s, 3H), 2.50 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.71, 153.72,153.63, 146.40, 141.40, 141.18, 138.50, 133.78, 131.33, 130.65, 130.56,129.89, 129.65, 127.48, 123.60, 122.11, 121.68, 114.38, 72.13, 51.98,18.23; HRMS (ESI-TOF) m/z Calcd for C₂₁H₁₉ClNO₃ [M+H]⁺: 368.1048, found:368.1053.

Methyl2-(4-((3-methylpyridin-2-yl)methoxy)-5,6,7,8-tetrahydronaphthalen-2-yl)benzoate(7i)

Substrate 3i was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7i was obtained in 90% yield as a light yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=4.7 Hz, 1H), 7.75 (d, J=7.9Hz, 1H), 7.54-7.46 m, 2H), 7.41-7.33 (m, 2H), 7.18 (dd, J=7.6, 4.8 Hz,1H), 6.82 (s, 1H), 6.68 (s, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 2.78-2.74(m, 2H), 2.71-2.65 (m, 2H), 2.43 (s, 3H), 1.82-1.72 m, 4H); ¹³C NMR (100MHz, CDCl₃) δ 169.50, 156.15, 154.63, 146.45, 142.35, 138.65, 138.27,138.14, 133.37, 131.08, 130.98, 130.58, 129.38, 126.80, 125.29, 123.33,121.58, 108.53, 71.05, 51.99, 29.67, 23.04, 22.79, 22.70, 18.19; HRMS(ESI-TOF) m/z Calcd for C₂₅H₂₆NO₃ [M+H]⁺: 388.1907, found: 388.1910.

Methyl 2-(4-((3-methylpyridin-2-yl)methoxy)naphthalen-2-yl)benzoate (7j)

Substrate 3j was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7j was obtained in 87% yield as a yellowliquid. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=4.8, 1.5 Hz, 1H), 8.24 (d,J=8.2 Hz, 1H), 7.84 (dd, J=7.6 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H),7.59-7.52 (m, 2H), 7.51-7.40 (m, 4H), 7.39 (s, 1H), 7.23 (dd, J=7.7, 4.9Hz, 1H), 7.02 (d, J=1.4 Hz, 1H), 5.38 (s, 2H), 3.55 (s, 3H), 2.47 (s,3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.27, 154.25, 154.04, 146.57, 142.43,139.06, 138.40, 134.23, 133.52, 131.19, 131.15, 130.84, 129.71, 127.66,127.22, 126.70, 125.25, 124.76, 123.52, 121.98, 119.70, 106.67, 71.33,51.97, 18.23; HRMS (ESI-TOF) m/z Calcd for C₂₅H₂₂NO₃ [M+H]⁺: 384.1594,found: 384.1598.

Methyl 2-(6-((3-methylpyridin-2-yl)methoxy)-2,3-dihydro-1H-inden-4-yl)benzoate (7k)

Substrate 3k was arylated following the general meta-arylation procedurefor phenols. After purification by preparative thin-layerchromatography, Compound 7k was obtained in 42% yield as a clear liquid.¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=4.9 Hz, 1H), 7.88 (d, J=7.8 Hz,1H), 7.54-7.48 (m, 2H), 7.39 (t, J=7.6 Hz, 1H), 7.31-7.23 (m, 1H), 7.18(dd, J=7.7, 4.8 Hz, 1H), 6.92 (s, 1H), 6.69 (d, J=2.3 Hz, 1H), 5.18 (s,2H), 3.62 (s, 3H), 2.93 (t, J=7.4 Hz, 2H), 2.55 (t, J=7.3 Hz, 2H), 2.43(s, 3H), 2.06-1.94 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 168.28, 157.49,154.57, 146.50, 145.21, 142.14, 138.50, 138.34, 134.70, 133.27, 131.35,130.67, 130.38, 129.80, 127.03, 123.32, 113.01, 109.93, 71.11, 51.94,33.41, 31.11, 25.59, 18.21; HRMS (ESI-TOF) m/z Calcd for C₂₄H₂₄NO₃[M+H]⁺: 374.1757, found: 374.1757.

Methyl2′-methoxy-5′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(7l)

Substrate 3l was arylated following the general meta-arylation procedurefor phenols. Analysis of crude reaction mixture by ¹H NMR showed theselectivity of mono- and di-products (mono:di=20>1). After purificationby preparative thin-layer chromatography, Compound 71 was obtained in58% yield as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.45 (d,J=4.3 Hz, 1H), 7.85 (dd, J=7.7, 1.4 Hz, 1H), 7.57-7.49 (m, 2H), 7.39(td, J=7.6, 1.2 Hz, 1H), 7.31 (dd, J=7.6, 1.3 Hz, 1H), 7.19 (dd, J=7.6,4.8 Hz, 1H), 7.02-6.96 (m, 2H), 6.80 (d, J=8.5 Hz, 1H), 5.19 (s, 2H),3.63-3.68 (m, 6H), 2.44 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.52,154.52, 152.76, 150.57, 146.55, 138.40, 138.36, 133.23, 131.62, 131.51,131.37, 131.20, 129.30, 127.18, 123.36, 117.34, 114.11, 111.00, 71.48,55.73, 51.68, 18.21; HRMS (ESI-TOF) m/z Calcd for C₂₂H₂₂NO₄ [M+H]⁺:364.1543, found: 364.1543.

Meta-Arylation of Other Heterocyclic Substrates

General Procedure for Meta-Arylation of Other Heterocycle Substrates:

Substrate 4 (0.1 mmol), methyl 2-iodobenzoate (43.0 μL, 0.3 mmol),Pd(OAc)₂ (2.2 mg, 10 mol %), L14 (4.4 mg, 20 mol %), AgOAc (50.1 mg, 0.3mmol), 2-Norbornene (14.1 mg, 0.15 mmol) and CHCl₃ (1.0 mL) were addedto a 2-dram vial. The vial was capped and closed tightly. Then thereaction mixture was then stirred at 90° C. for 24 hours. After coolingto room temperature, the mixture was passed through a pad of Celite®with DCM as the eluent to remove the insoluble precipitate. Theresultant solution was concentrated and purified by preparative TLC toafford the desired arylated product. (In cases where mono:di ratios arepossible, the selectivity was determined by ¹H NMR.)

Methyl 3′-(pyridin-2-ylmethyl)-[1,1′-biphenyl]-2-carboxylate (8a)

Substrate 4a was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di=2:1). Afterpurification by preparative thin-layer chromatography, Compounds 8a and8a′ were obtained in 92% total yield.

¹H NMR (400 MHz, CDCl₃) δ 8.58-8.53 (m, 1H), 7.79 (d, J=7.5 Hz, 1H),7.58 (td, J=7.7, 1.8 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.42-7.31 (m, 3H),7.30-7.24 (m, 1H), 7.23-7.16 (m, 2H), 7.16-7.08 (m, 2H), 4.19 (s, 2H),3.55 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 169.11, 160.85, 149.30, 142.23,141.50, 139.17, 136.53, 131.15, 130.88, 130.64, 129.66, 129.10, 128.30,128.04, 127.09, 126.38, 123.11, 121.25, 51.84, 44.62; HRMS (ESI-TOF) m/zCalcd for C₂₀H₁₈NO₂ [M+H]⁺: 304.1332, found: 304.1332.

Dimethyl5′-(pyridin-2-ylmethyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate (8a′)

¹H NMR (400 MHz, CDCl₃) δ 8.55 (d, J=3.6 Hz, 1H), 7.82-7.76 (m, 2H),7.60 (td, J=7.7, 1.8 Hz, 1H), 7.54-7.47 (m, 2H), 7.43-7.36 (m, 4H), 7.20(s, 2H), 7.19-7.15 (m, 2H), 7.12 (dd, J=7.5, 5.0 Hz, 1H), 4.23 (s, 2H),3.58 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 169.10, 160.77, 149.30, 141.94,141.44, 138.84, 136.54, 131.15, 131.02, 130.67, 129.70, 128.12, 127.19,126.46, 123.13, 121.30, 51.87, 44.56; HRMS (ESI-TOF) m/z Calcd forC₂₈H₂₄NO₄ [M+H]⁺: 438.1700, found: 438.1698.

Dimethyl5′-(pyridin-2-ylmethyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate (8b)

Substrate 4b was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 8b was obtained in 92% yield. ¹H NMR (400 MHz,CDCl₃) δ 8.55-8.49 (m, 1H), 8.00 (d, J=7.9 Hz, 1H), 7.84 (dd, J=7.7, 1.4Hz, 1H), 7.59-7.48 (m, 2H), 7.42 (td, J=7.6, 1.3 Hz, 1H), 7.35 (dd,J=7.6, 1.3 Hz, 1H), 7.30-7.24 (m, 2H), 7.12-7.04 (m, 2H), 4.61 (s, 2H),3.83 (s, 3H), 3.59 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 168.53, 167.72,160.74, 149.08, 145.28, 141.29, 140.29, 136.36, 132.08, 131.38, 130.72,130.56, 130.54, 129.98, 128.63, 127.70, 126.57, 122.88, 121.04, 51.96,51.95, 42.53; HRMS (ESI-TOF) m/z Calcd for C₂₂H₂₀NO₄ [M+H]⁺: 362.1387,found: 362.1387.

Dimethyl5′-((3-methylpyridin-2-yl)methyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(8c′)

Substrate 4c was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 8c′ was obtained in 55% total yield as a soleproduct.

¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J=4.5 Hz, 1H), 7.77 (d, J=7.5 Hz,2H), 7.49 (t, J=7.5 Hz, 2H), 7.43 (d, J=7.3 Hz, 1H), 7.41-7.34 (m, 4H),7.14-7.06 (m, 4H), 4.26 (s, 2H), 3.57 (s, 6H), 2.29 (s, 3H); ¹³C NMR(150 MHz, CDCl₃) δ 169.11, 158.50, 146.81, 142.01, 141.26, 138.57,138.06, 131.84, 131.12, 131.03, 130.69, 129.66, 127.59, 127.14, 126.23,121.85, 51.85, 42.24, 19.06; HRMS (ESI-TOF) m/z Calcd for C₂₉H₂₆NO₄[M+H]⁺: 452.1856, found: 452.1856.

Dimethyl5′-((5-methylpyridin-2-yl)methyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(8d′)

Substrate 4d was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 8d′ was obtained in 60% yield as a soleproduct. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d, J=2.2 Hz, 1H), 7.82-7.76 (m,2H), 7.50 (td, J=7.5, 1.4 Hz, 2H), 7.43-7.35 (m, 5H), 7.18 (d, J=1.6 Hz,2H), 7.14 (t, J=1.6 Hz, 1H), 7.05 (d, J=7.9 Hz, 1H), 4.18 (s, 2H), 3.59(s, 6H), 2.29 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.13, 157.76,149.61, 141.99, 141.38, 139.18, 137.13, 131.13, 131.02, 130.69, 130.55,129.69, 128.07, 127.17, 126.38, 122.61, 51.87, 44.07, 18.01; HRMS(ESI-TOF) m/z Calcd for C₂₉H₂₆NO₄ [M+H]⁺: 452.1856, found: 452.1855.

Methyl 3′-(pyrimidin-2-ylmethyl)-[1,1′-biphenyl]-2-carboxylate (8e)

Substrate 4e was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di=4:1). Afterpurification by preparative thin-layer chromatography, Compounds 8e and8e′ were obtained in 64% total yield. ¹H NMR (600 MHz, CDCl₃) δ 8.68 (d,J=4.9 Hz, 2H), 7.78 (ddd, J=7.7, 1.4, 0.6 Hz, 1H), 7.50 (td, J=7.6, 1.4Hz, 1H); 7.41-7.32 (m, 4H), 7.31-7.29 (m, 1H), 7.18 (dt, J=6.9, 1.8 Hz,1H), 7.13 (t, J=4.9 Hz, 1H), 4.33 (s, 2H), 3.57 (s, 3H); ¹³C NMR (150MHz, CDCl₃) δ 169.89, 169.20, 157.29, 142.20, 141.40, 137.99, 131.13,130.93, 130.69, 129.65, 129.10, 128.20, 128.05, 127.08, 126.59, 118.69,51.87, 45.99; HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₇N₂O₂ [M+H]⁺: 305.1285,found: 305.1284.

Dimethyl5′-(pyrimidin-2-ylmethyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(8e′)

¹H NMR (400 MHz, CDCl₃) δ 8.69 (d, J=4.9 Hz, 2H), 7.79 (d, J=7.5 Hz,2H), 7.50 (t, J=7.5 Hz, 2H), 7.42-7.36 (m, 4H), 7.28 (s, 2H), 7.26 (s,1H), 7.17-7.12 (m, 1H), 4.36 (s, 2H), 3.59 (s, 6H); ¹³C NMR (150 MHz,CDCl₃) δ 169.75, 169.22, 157.29, 141.93, 141.28, 137.74, 131.14, 131.05,130.72, 129.69, 128.06, 127.17, 126.63, 118.77, 51.89, 45.86; HRMS(ESI-TOF) m/z Calcd for C₂₇H₂₃N₂O₄ [M+H]⁺: 439.1652, found: 439.1652.

Methyl 3′-(pyrazin-2-ylmethyl)-[1,1′-biphenyl]-2-carboxylate (8f)

Substrate 4f was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di=2:1). Afterpurification by preparative thin-layer chromatography, Compounds 8f and8f′ were obtained in 84% total yield.

¹H NMR (400 MHz, CDCl₃) δ 8.51 (d, J=2.0 Hz, 1H), 8.48 (s, 1H), 8.42 (d,J=2.5 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.4 Hz, 1H), 7.40 (t,J=8.0 Hz, 1H), 7.35 (d, J=7.6 Hz, 2H), 7.24-7.18 (m, 1H), 7.21 (d, J=8.0Hz, 2H), 4.21 (s, 2H), 3.59 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 168.97,156.41, 144.78, 144.08, 142.41, 142.09, 141.83, 137.81, 131.23, 130.79,130.66, 129.76, 129.02, 128.48, 127.92, 127.23, 126.83, 51.92, 41.96;HRMS (ESI-TOF) m/z Calcd for C₁₉H₁₇N₂O₂ [M+H]⁺: 305.1285, found:305.1285.

Dimethyl5′-(pyrazin-2-ylmethyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate (8f′)

¹H NMR (400 MHz, CDCl₃) δ 8.52 (d, J=1.6 Hz, 1H), 8.49 (s, 1H), 8.43 (d,J=2.6 Hz, 1H), 7.81 (d, J=7.7 Hz, 2H), 7.54-7.48 (m, 2H), 7.44-7.36 (m,4H), 7.20 (s, 2H), 7.17 (s, 1H), 4.25 (s, 2H), 3.61 (s, 6H); ¹³C NMR(150 MHz, CDCl₃) δ 168.97, 156.39, 144.81, 144.07, 142.45, 141.82,141.76, 137.46, 131.24, 130.94, 130.70, 129.82, 128.01, 127.34, 126.91,51.97, 41.95; HRMS (ESI-TOF) m/z Calcd for C₂₇H₂₃N₂O₄ [M+H]⁺: 439.1652,found: 439.1652.

Methyl 3′-((1H-pyrazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (8g)

Substrate 4g was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di=1:2). Afterpurification by preparative thin-layer chromatography, Compounds 8g and8g′ were obtained in 84% total yield.

¹H NMR (400 MHz, CDCl₃) δ 8.69 (d, J=4.9 Hz, 2H), 7.78 (d, J=7.7 Hz,1H), 7.54-7.47 (m, 1H), 7.42-7.28 (m, 5H), 7.22-7.16 (m, 1H), 7.14 (t,J=4.9 Hz, 1H), 4.33 (s, 2H), 3.57 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ169.89, 169.22, 157.30, 142.20, 141.41, 137.99, 131.14, 130.92, 130.70,129.66, 129.10, 128.21, 128.05, 127.08, 126.60, 118.70, 51.88, 45.98;HRMS (ESI-TOF) m/z Calcd for C₁₈H₁₇N₂O₂ [M+H]⁺: 293.1285, found:293.1285.

Dimethyl5′-((1H-pyrazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(8g′)

¹H NMR (400 MHz, CDCl₃) δ 7.82 (d, J=7.7 Hz, 2H), 7.57-7.48 (m, 3H),7.45-7.35 (m, 5H), 7.22 (s, 1H), 7.15 (s, 2H), 6.29 (t, J=2.2 Hz, 1H),5.39 (s, 2H), 3.62 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 168.80, 141.77,141.64, 139.57, 136.00, 131.30, 130.82, 130.72, 129.88, 129.26, 128.10,127.43, 126.71, 106.00, 55.79, 51.99; HRMS (ESI-TOF) m/z Calcd forC₂₆H₂₃N₂O₄ [M+H]⁺: 427.1652, found: 427.1652.

Methyl 3′-(N-(pyridin-2-yl)acetamido)-[1,1′-biphenyl]-2-carboxylate (8h)

Substrate 4h was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 8h was obtained in 60% yield as a sole product.¹H NMR (400 MHz, CDCl₃) δ 8.47-8.40 (m, 1H), 7.83 (dd, J=7.7, 1.4 Hz,1H), 7.72 (td, J=7.8, 2.0 Hz, 1H), 7.57-7.35 (m, 5H), 7.35-7.28 (m, 2H),7.22 (t, J=2.0 Hz, 1H), 7.17-7.10 (m, 1H), 3.59 (s, 3H), 2.15 (s, 3H);¹³C NMR (150 MHz, CDCl₃) δ 171.03, 168.60, 155.16, 148.74, 142.68,141.62, 141.37, 137.92, 131.38, 130.72, 130.60, 129.95, 129.14, 128.61,127.52, 127.23, 121.43, 121.16, 51.97, 24.29; HRMS (ESI-TOF) m/z Calcdfor C₂₁H₁₉N₂O₃ [M+H]⁺: 347.1390, found: 347.1389.

Methyl3′-((tert-butoxycarbonyl)(pyrimidin-2-yl)amino)-[1,1′-biphenyl]-2-carboxylate(8i)

Substrate 4i was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, 8i was obtained in 50% yield as a sole product. ¹H NMR(400 MHz, CDCl₃) δ 8.66 (d, J=4.8 Hz, 2H), 7.82-7.77 (m, 1H), 7.51 (td,J=7.6, 1.4 Hz, 1H), 7.45-7.34 (m, 3H), 7.26-7.21 (m, 2H), 7.15 (t, J=2.0Hz, 1H), 7.05 (t, J=4.8 Hz, 1H), 3.61 (s, 3H), 1.46 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 169.03, 161.28, 158.23, 153.14, 142.15, 141.49,141.01, 131.21, 130.97, 130.62, 130.05, 129.77, 128.53, 127.61, 127.34,126.79, 126.56, 117.27, 82.07, 51.95, 28.07; HRMS (ESI-TOF) m/z Calcdfor C₂₃H₂₄N₃O₄ [M+H]⁺: 406.1761, found: 406.1761.

Methyl 3′-((2H-indazol-2-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (8j)

Substrate 4j was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di=3:1). Afterpurification by preparative thin-layer chromatography, Compounds 8j and8j′ were obtained in 74% total yield. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d,J=0.9 Hz, 1H), 7.82-7.76 (m, 1H), 7.78-7.70 (m, 1H), 7.49 (td, J=7.5,1.4 Hz, 1H), 7.43-7.27 (m, 5H), 7.24-7.10 (m, 4H), 5.64 (s, 2H), 3.47(d, J=0.5 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.82, 141.96, 141.83,139.52, 136.68, 133.39, 131.24, 130.75, 130.68, 129.79, 128.43, 127.80,127.28, 127.22, 126.38, 126.12, 124.38, 121.14, 120.64, 109.29, 52.96,51.80; HRMS (ESI-TOF) m/z Calcd for C₂₂H₁₉N₂O₂ [M+H]⁺: 343.1441, found:343.1442.

Dimethyl5′-((2H-indazol-2-yl)methyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(8j′)

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.79 (d, J=7.5 Hz, 2H), 7.74 (d,J=8.0 Hz, 1H), 7.49 (t, J=7.3 Hz, 2H), 7.43-7.31 (m, 6H), 7.15 (d,J=11.4 Hz, 4H), 5.66 (s, 2H), 3.49 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ168.82, 141.73, 141.66, 139.49, 136.42, 133.40, 131.23, 130.88, 130.72,129.83, 127.90, 127.37, 126.38, 126.25, 124.42, 121.16, 120.67, 109.33,52.97, 51.82; HRMS (ESI-TOF) m/z Calcd for C₃₀H₂₅N₂O₄ [M+H]⁺: 477.1809,found: 477.1810.

Methyl 3′-((1H-indazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylate (8k)

Substrate 4k was arylated following the general meta-arylation procedureusing 2-norbornene. Analysis of crude reaction mixture by ¹H NMR showedthe selectivity of mono- and di-products (mono:di=3:1). Afterpurification by preparative thin-layer chromatography, 8k and 8k′ wasobtained in 50% total yield.

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.74 (d,J=8.1 Hz, 1H), 7.48 (td, J=7.6, 1.4 Hz, 1H), 7.41-7.26 (m, 5H),7.24-7.10 (m, 4H), 5.63 (s, 2H), 3.47 (s, 3H); ¹³C NMR (100 MHz, CDCl₃)δ 168.81, 141.94, 141.81, 139.51, 136.68, 133.38, 131.23, 130.74,130.67, 129.78, 128.43, 127.79, 127.26, 127.21, 126.37, 126.11, 124.37,121.13, 120.63, 109.28, 52.94, 51.79; HRMS (ESI-TOF) m/z Calcd forC₂₂H₁₉N₂O₂ [M+H]⁺: 343.1441, found: 343.1440.

Dimethyl5′-((1H-indazol-1-yl)methyl)-[1,1′:3′1″-terphenyl]-2,2″-dicarboxylate(8k′)

¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 1H), 7.79 (d, J=7.9 Hz, 2H), 7.74 (d,J=8.1 Hz, 1H), 7.49 (t, J=7.4 Hz, 2H), 7.44-7.31 (m, 6H), 7.20-7.10 (m,4H), 5.66 (s, 2H), 3.49 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 168.81,141.73, 141.66, 139.49, 136.42, 133.40, 131.23, 130.88, 130.72, 129.83,127.90, 127.37, 126.38, 126.25, 124.42, 121.16, 120.67, 109.33, 52.97,51.82; HRMS (ESI-TOF) m/z Calcd for C₃₀H₂₅N₂O₄ [M+H]⁺: 477.1809, found:477.1808.

Dimethyl5′-(isoquinolin-1-ylmethyl)-[1,1′:3′,1″-terphenyl]-2,2″-dicarboxylate(8l′)

Substrate 4l was arylated following the general meta-arylation procedureusing 2-norbornene. After purification by preparative thin-layerchromatography, Compound 8l′ was obtained in 78% yield as a soleproduct. ¹H NMR (400 MHz, CDCl₃) δ 8.49 (d, J=5.7 Hz, 1H), 8.21 (d,J=8.4 Hz, 1H), 7.82 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.7 Hz, 2H), 7.64 (t,J=7.5 Hz, 1H), 7.60-7.53 (m, 2H), 7.48 (t, J=7.9 Hz, 2H), 7.41-7.32 (m,4H), 7.22 (s, 2H), 7.10 (s, 1H), 4.73 (s, 2H), 3.41 (s, 6H); ¹³C NMR(150 MHz, CDCl₃) δ 169.07, 159.85, 142.02, 141.89, 141.41, 139.00,136.61, 131.11, 131.03, 130.67, 129.86, 129.66, 127.57, 127.36, 127.23,127.17, 127.14, 126.37, 125.90, 119.90, 51.70, 42.12; HRMS (ESI-TOF) m/zCalcd for C₃₂H₂₆NO₄ [M+H]⁺: 488.1856, found: 488.1857.

Scope of Aryl Iodides

General Procedure for Meta-Arylation of Anilines:

Substrate 1a (0.1 mmol), Ar—I (0.2 mmol), Pd(OAc)₂ (2.2 mg, 10 mol %),Ligand (3.0 mg, 20 mol %), AgOAc (50.1 mg, 0.3 mmol), NBE-CO₂Me (21.6mg, 0.15 mmol) and DCE (0.5 mL) were added to a 2-dram vial. The vialwas capped and closed tightly. The reaction mixture was then stirred at100° C. for 24 hours. After cooling to room temperature, the mixture waspassed through a pad of Celite® with DCM as the eluent to remove theinsoluble precipitate. The resulting solution was concentrated andpurified by preparative TLC plate to afford the desired arylatedproduct.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-methyl-[1,1′-biphenyl]-3-yl)carbamate(9a)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9a was obtained in 87% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.47 (d, J=7.5 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H),7.29 (t, J=7.3 Hz, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 4.94(s, 2H), 3.71 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.41 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.64, 155.20, 154.75, 148.96, 143.04, 141.14,141.05, 138.35, 128.55, 127.08, 125.85, 125.23, 124.64, 123.74, 122.61,80.25, 59.82, 53.55, 28.30, 21.46, 13.19, 10.44; HRMS (ESI-TOF) m/zCalcd for C₂₇H₃₃N₂O₃ [M+H]⁺: 433.2486, found: 433.2487.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-methyl-[1,1′:4′,1″-terphenyl]-3-yl)carbamate (9b)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9b was obtained in 79% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.19 (s, 1H), 7.62 (d, J=8.0 Hz, 4H), 7.56 (d, J=8.1 Hz, 2H),7.44 (t, J=7.6 Hz, 2H), 7.34 (t, J=7.3 Hz, 1H), 7.29 (s, 1H), 7.19 (s,1H), 7.09 (s, 1H), 4.95 (s, 2H), 3.72 (s, 3H), 2.35 (s, 3H), 2.23 (s,3H), 2.21 (s, 3H), 1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) 5163.65,155.20, 154.75, 148.97, 143.13, 140.67, 140.60, 139.94, 138.41, 137.83,128.74, 127.41, 127.29, 127.25, 126.97, 125.97, 125.09, 124.65, 123.73,122.48, 80.26, 59.82, 53.54, 28.30, 21.48, 13.19, 10.44; HRMS (ESI-TOF)m/z Calcd for C₃₃H₃₇N₂O₃ [M+H]⁺: 509.2799, found: 509.2799.

tert-Butyl(4′,5-dimethyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9c)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9c was obtained in 82% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.37 (d, J=7.9 Hz, 2H), 7.23-7.21 (m, 3H), 7.13(s, 1H), 7.04 (s, 1H), 4.93 (s, 2H), 3.71 (s, 3H), 2.36 (s, 3H), 2.32(s, 3H), 2.21 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.63,155.21, 154.77, 148.94, 142.99, 141.04, 138.26, 138.15, 136.82, 129.26,129.24, 126.89, 125.60, 125.04, 124.61, 123.73, 122.40, 80.20, 59.81,53.55, 28.29, 28.26, 21.45, 21.05, 13.17, 10.42; HRMS (ESI-TOF) m/zCalcd for C₂₈H₃₅N₂O₃ [M+H]⁺: 447.2642, found: 447.2643.

tert-Butyl(4′-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9d)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9d was obtained in 83% yield as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H),7.21 (s, 1H), 7.14 (s, 1H), 7.05 (s, 1H), 4.94 (s, 2H), 4.76 (s, 2H),3.71 (s, 3H), 2.33 (s, 3H), 2.21 (s, 3H), 2.21 (s, 3H), 1.41 (s, 9H),0.95 (s, 9H), 0.11 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 163.65, 155.19,154.76, 148.95, 142.98, 140.98, 140.34, 139.66, 138.30, 126.89, 126.29,125.75, 125.15, 124.64, 123.77, 122.51, 80.23, 64.73, 59.81, 53.54,28.29, 25.95, 21.46, 18.42, 13.18, 10.44, −5.24; HRMS (ESI-TOF) m/zCalcd for C₃₄H₄₉N₂O₄Si [M+H]⁺: 577.3456, found: 577.3456.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(4′-methoxy-5-methyl-[1,1′-biphenyl]-3-yl)carbamate(9e)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9e was obtained in 81% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.19 (s, 1H), 7.10 (s,1H), 7.02 (s, 1H), 6.92 (d, J=8.5 Hz, 2H), 4.93 (s, 2H), 3.83 (s, 3H),3.71 (s, 3H), 2.32 (s, 3H), 2.21 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.63, 158.98, 155.22, 154.77, 148.94, 143.01, 140.72,138.27, 133.59, 128.06, 125.28, 124.82, 124.62, 123.74, 122.17, 113.98,80.20, 59.82, 55.29, 53.55, 28.30, 21.46, 13.19, 10.43; HRMS (ESI-TOF)m/z Calcd for C₂₈H₃₅N₂O₄ [M+H]⁺: 463.2591, found: 463.2591.

tert-Butyl(4′-((tert-butyldimethylsilyl)oxy)-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl)carbamate(9f)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9f was obtained in 65% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.34 (d, J=8.3 Hz, 2H), 7.18 (s, 1H), 7.10 (s,1H), 7.01 (s, 1H), 6.84 (d, J=8.2 Hz, 2H), 4.94 (s, 2H), 3.71 (s, 3H),2.31 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.41 (s, 9H), 0.99 (s, 9H),0.21 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66, 155.23, 155.11, 154.77,148.92, 142.91, 140.82, 138.24, 134.12, 128.00, 125.30, 124.88, 124.64,123.82, 122.24, 120.14, 80.19, 59.81, 53.55, 28.30, 25.68, 21.45, 18.21,13.18, 10.45, −4.40; HRMS (ESI-TOF) m/z Calcd for C₃₃H₄₇N₂O₄Si [M+H]⁺:563.3300, found: 563.3300.

tert-Butyl(4′-((diethoxyphosphoryl)methyl)-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl)carbamate(9g)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9g was obtained in 92% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.43 (d, J=7.9 Hz, 2H), 7.31 (dd, J=8.3, 2.5 Hz,2H), 7.23 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 4.94 (s, 2H), 4.12-3.94(m, 4H), 3.72 (s, 3H), 3.17 (d, J=21.6 Hz, 2H), 2.33 (s, 3H), 2.24-2.19(m, 6H), 1.41 (s, 9H), 1.26 (t, J=7.0 Hz, 6H); ¹³C NMR (150 MHz, CDCl₃)δ 163.63, 155.14, 154.72, 148.92, 143.06, 140.62, 139.56 (d, J=4.1 Hz),138.35, 130.43 (d, J=9.0 Hz), 129.95 (d, J=6.6 Hz), 127.15 (d, J=3.3Hz), 125.84, 125.03, 124.63, 123.71, 122.39, 80.25, 62.12 (d, J=7.1 Hz),59.81, 53.50, 33.36 (d, J=138.4 Hz), 28.26, 21.43, 16.35 (d, J=6.2 Hz),13.17, 10.41; HRMS (ESI-TOF) m/z Calcd for C₃₂H₄₄N₂O₆P [M+H]⁺: 583.2932,found: 583.2931.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-methyl-4′-(methylthio)-[1,1′-biphenyl]-3-yl)carbamate(9h)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9h was obtained in 70% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.27 (d, J=9.0 Hz, 2H),7.22 (s, 1H), 7.12 (s, 1H), 7.06 (s, 1H), 4.93 (s, 2H), 3.72 (s, 3H),2.50 (s, 3H), 2.33 (s, 3H), 2.21 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.65, 155.18, 154.74, 148.96, 143.14, 140.44, 138.42,137.90, 137.33, 127.41, 126.80, 125.81, 124.87, 124.64, 123.72, 122.26,80.27, 59.84, 53.54, 28.30, 21.47, 15.92, 13.20, 10.43; HRMS (ESI-TOF)m/z Calcd for C₂₈H₃₅N₂O₃S [M+H]⁺: 479.2363, found: 479.2362.

tert-Butyl(4′-(benzyl(tert-butoxycarbonyl)amino)-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9i)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9i was obtained in 80% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.16 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.33-7.27 (m, 2H),7.27-7.14 (m, 6H), 7.10 (s, 1H), 7.05 (s, 1H), 4.92 (s, 2H), 4.85 (s,2H), 3.70 (s, 3H), 2.31 (s, 3H), 2.24-2.16 m, 6H), 1.43 (s, 9H), 1.40(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.63, 155.14, 154.74, 154.71,148.94, 143.06, 141.90, 140.43, 138.61, 138.38, 138.33, 128.36, 127.29,127.21, 127.02, 126.38, 125.79, 125.00, 124.61, 123.68, 122.39, 80.61,80.24, 59.81, 53.89, 53.50, 28.26, 21.43, 13.17, 10.41; HRMS (ESI-TOF)m/z Calcd for C₃₉H₄₈N₃O₅ [M+H]⁺: 638.3588, found: 638.3588.

tert-Butyl(4′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9j)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9j was obtained in 92% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.47-7.39 (m, 2H), 7.21 (s, 1H), 7.12-7.02 (m,4H), 4.93 (s, 2H), 3.72 (s, 3H), 2.33 (s, 3H), 2.22 (s, 3H), 2.21 (s,3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.65, 162.31 (d, J=246.4Hz), 155.17, 154.69, 148.93, 143.13, 140.15, 138.45, 137.13, 128.59 (d,J=8.3 Hz), 125.82, 125.05, 124.65, 123.71, 122.45, 115.38 (d, J=21.1Hz), 80.29, 59.82, 53.51, 28.27, 21.43, 13.18, 10.42; ¹⁹F NMR (376 MHz,CDCl₃) δ −116.22; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₂FN₂O₃ [M+H]⁺:451.2391, found: 451.2391.

tert-Butyl(4′-chloro-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9k)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9k was obtained in 83% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.40 (d, J=8.6 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H),7.22 (s, 1H), 7.10 (s, 1H), 7.08 (s, 1H), 4.93 (s, 2H), 3.72 (s, 3H),2.33 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.66, 155.13, 154.67, 148.94, 143.20, 139.89, 139.48,138.55, 133.14, 128.69, 128.30, 126.14, 124.98, 124.68, 123.71, 122.39,80.33, 59.83, 53.49, 28.27, 21.44, 13.19, 10.42. HRMS (ESI-TOF) m/zCalcd for C₂₇H₃₂ClN₂O₃ [M+H]⁺: 467.2096, found: 467.2096.

tert-Butyl(4′-bromo-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9l)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9l was obtained in 82% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H),7.22 (s, 1H), 7.12-7.05 (m, 2H), 4.93 (s, 2H), 3.72 (s, 3H), 2.33 (s,3H), 2.25-2.18 (m, 6H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66,155.13, 154.67, 148.94, 143.24, 139.95, 139.90, 138.57, 131.64, 128.66,126.20, 124.92, 124.67, 123.69, 122.35, 121.31, 80.33, 59.83, 53.49,28.27, 21.43, 13.20, 10.42; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₂BrN₂O₃[M+H]⁺: 511.1591, found: 511.1592.

tert-Butyl(4′-iodo-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9m)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9m was obtained in 67% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.16 (s, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.25-7.17 (m, 3H), 7.09(s, 2H), 4.93 (s, 2H), 3.72 (s, 3H), 2.33 (s, 3H), 2.21 (s, 6H), 1.40(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66, 155.12, 154.67, 148.95,143.25, 140.56, 139.96, 138.59, 137.63, 128.94, 126.26, 124.87, 124.68,123.71, 122.30, 92.81, 80.34, 59.84, 53.49, 28.27, 21.44, 13.20, 10.43;HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₂IN₂O₃ [M+H]⁺: 559.1452, found:559.1451.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-methyl-[1,1′-biphenyl]-4-carboxylate(9n)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9n was obtained in 92% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H),7.29 (s, 1H), 7.18 (s, 1H), 7.12 (s, 1H), 4.94 (s, 2H), 3.93 (s, 3H),3.72 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 166.96, 163.70, 155.08, 154.65, 148.92,145.47, 143.22, 139.92, 138.63, 129.90, 128.69, 126.96, 126.73, 125.26,124.73, 123.76, 122.71, 80.38, 59.83, 53.45, 52.06, 28.26, 21.43, 13.19,10.43; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₅N₂O₅ [M+H]⁺: 491.2540, found:491.2541.

tert-Butyl(4′-acetyl-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9o)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9o was obtained in 87% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.98 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H),7.31 (s, 1H), 7.18 (s, 1H), 7.13 (s, 1H), 4.94 (s, 2H), 3.72 (s, 3H),2.62 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 197.71, 163.67, 155.08, 154.65, 148.95,145.64, 143.31, 139.79, 138.66, 135.69, 128.72, 127.14, 126.79, 125.22,124.70, 123.69, 122.68, 80.39, 59.83, 53.47, 28.26, 26.61, 21.44, 13.19,10.42; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₅N₂O₄ [M+H]⁺: 475.2591, found:475.2591.

tert-Butyl(4′-formyl-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9p)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9p was obtained in 96% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 10.03 (s, 1H), 8.18 (s, 1H), 7.90 (d, J=8.1 Hz, 2H), 7.64 (d,J=8.1 Hz, 2H), 7.33 (s, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 4.94 (s, 2H),3.73 (s, 3H), 2.36 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 191.90, 163.69, 155.08, 154.63, 148.96,147.08, 143.38, 139.65, 138.77, 135.05, 130.10, 127.62, 127.02, 125.31,124.74, 123.71, 122.79, 80.44, 59.85, 53.47, 28.26, 21.45, 13.21, 10.44;HRMS (ESI-TOF) m/z Calcd for C₂₈H₃₃N₂O₄ [M+H]⁺: 461.2435, found:461.2436.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamate(9q)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9q was obtained in 97% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H),7.29 (s, 1H), 7.19-7.09 (m, 2H), 4.94 (s, 2H), 3.72 (s, 3H), 2.35 (s,3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 163.68, 155.10, 154.65, 148.96, 144.57, 143.36, 139.68, 138.71, 129.14(q, J=32.6 Hz), 127.34, 126.70, 125.50 (q, J=3.4 Hz), 125.22, 124.71,124.21 (q, J=271.8 Hz); 123.69, 122.69, 80.41, 59.84, 53.47, 28.26,21.43, 13.20, 10.42; ¹⁹F NMR (376 MHz, CDCl₃) δ −62.62; HRMS (ESI-TOF)m/z Calcd for C₂₈H₃₂F₃N₂O₃ [M+H]⁺: 501.2360, found: 501.2360.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-methyl-4′-nitro-[1,1′-biphenyl]-3-yl)carbamate (9r)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9r was obtained in 88% yield as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.24 (d, J=8.6 Hz, 2H), 8.18 (s, 1H), 7.63 (d, J=8.6 Hz, 2H),7.36 (s, 1H), 7.22-7.15 (m, 2H), 4.94 (s, 2H), 3.74 (s, 3H), 2.36 (s,3H), 2.23 (s, 3H), 2.23 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 163.70, 155.02, 154.57, 148.96, 147.50, 146.91, 143.57, 138.96,138.69, 127.72, 127.37, 125.24, 124.77, 123.92, 123.67, 122.76, 80.53,59.87, 53.41, 28.24, 21.44, 13.22, 10.42; HRMS (ESI-TOF) m/z Calcd forC₂₇H₃₂N₃O₅ [M+H]⁺: 478.2336, found: 478.2336.

tert-Butyl(4′-cyano-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9s)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9s was obtained in 89% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H),7.31 (s, 1H), 7.19-7.12 (m, 2H), 4.93 (s, 2H), 3.73 (s, 3H), 2.35 (s,3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.40 (s, 9H); ¹³C NMR (150 MHz, CDCl₃)δ 163.70, 155.02, 154.57, 148.93, 145.53, 143.47, 139.11, 138.89,132.41, 127.67, 127.12, 125.12, 124.76, 123.70, 122.61, 118.94, 110.68,80.49, 59.86, 53.39, 28.24, 21.43, 13.21, 10.42; HRMS (ESI-TOF) m/zCalcd for C₂₈H₃₂N₃O₃ [M+H]⁺: 458.2438, found: 458.2438.

Methyl3′-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5′-methyl-[1,1′-biphenyl]-3-carboxylate(9t)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9t was obtained in 88% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 2H), 7.98 (d, J=7.7 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H),7.46 (t, J=7.7 Hz, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 4.95(s, 2H), 3.94 (s, 3H), 3.72 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H), 2.21(s, 3H), 1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 167.01, 163.68,155.10, 154.69, 148.95, 143.19, 141.30, 140.03, 138.60, 131.50, 130.48,128.66, 128.20, 126.24, 125.18, 124.69, 123.75, 122.64, 80.37, 59.83,53.47, 52.13, 28.28, 21.44, 13.19, 10.44; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₅N₂O₅ [M+H]⁺: 491.2540, found: 491.2541.

tert-Butyl(3′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9u)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9u was obtained in 86% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.38-7.28 (m, 1H), 7.25 (d, J=6.2 Hz, 1H), 7.20(s, 1H), 7.18-7.07 (m, 3H), 6.98 (td, J=7.7, 2.1 Hz, 1H), 4.94 (s, 2H),3.72 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 163.69, 163.01 (d, J=245.4 Hz), 155.15,154.68, 148.97, 143.33 (d, J=7.6 Hz), 143.15, 139.86, 138.57, 129.98 (d,J=8.6 Hz), 126.47, 125.14, 124.73, 123.79, 122.68 (d, J=2.6 Hz), 122.60,113.95 (d, J=10.8 Hz), 113.81 (d, J=9.9 Hz), 80.34, 59.82, 53.52, 28.27,21.43, 13.18, 10.44; ¹⁹F NMR (376 MHz, CDCl₃) 5-113.61; HRMS (ESI-TOF)m/z Calcd for C₂₇H₃₂FN₂O₃ [M+H]⁺: 451.2391, found: 451.2391.

tert-Butyl(3′-iodo-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9v)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9v was obtained in 74% yield as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.80 (d, J=1.7 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H),7.43 (d, J=7.8 Hz, 1H), 7.17 (s, 1H), 7.14-7.06 (m, 3H), 4.93 (s, 2H),3.73 (s, 3H), 2.33 (s, 3H), 2.22 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.70, 155.11, 154.67, 148.97, 143.29, 143.12, 139.53,138.60, 136.08, 135.97, 130.22, 126.44, 126.34, 125.14, 124.73, 123.81,122.59, 94.57, 80.37, 77.21, 59.88, 53.51, 28.29, 21.43, 13.25, 10.46;HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₂IN₂O₃ [M+H]⁺: 559.1452, found:559.1453.

tert-Butyl(3′,5-dimethyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9w)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9w was obtained in 82% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.31-7.23 (m, 3H), 7.20 (s, 1H), 7.16-7.09 (m,2H), 7.05 (s, 1H), 4.94 (s, 2H), 3.71 (s, 3H), 2.38 (s, 3H), 2.33 (s,3H), 2.25-2.19 (m, 6H), 1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66,155.23, 154.77, 148.94, 142.95, 141.26, 141.02, 138.28, 138.06, 128.44,127.88, 127.83, 125.79, 125.27, 124.62, 124.17, 123.79, 122.67, 80.21,59.81, 53.56, 28.30, 21.49, 21.45, 13.18, 10.44; HRMS (ESI-TOF) m/zCalcd for C₂₈H₃₅N₂O₃ [M+H]⁺: 447.2642, found: 447.2643.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3′-methoxy-5-methyl-[1,1′-biphenyl]-3-yl)-carbamate(9x)

Following the general meta-acylation procedure using NEE-CO₂Me, Compound9x was obtained in 85% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.21 (s, 1H), 7.14 (s,1H), 7.11-7.02 (m, 2H), 6.99 (t, J=2.1 Hz, 1H), 6.85 (dd, J=8.2, 2.5 Hz,1H), 4.94 (s, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 2.33 (s, 3H), 2.22 (s,3H), 2.21 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66,159.76, 155.18, 154.75, 148.95, 143.01, 142.59, 141.01, 138.34, 129.52,126.05, 125.26, 124.66, 123.77, 122.67, 119.61, 112.80, 112.54, 80.25,59.82, 55.24, 53.54, 28.30, 21.45, 13.18, 10.43; HRMS (ESI-TOF) m/zCalcd for C₂₈H₃₅N₂O₄ [M+H]⁺: 463.2591, found: 463.2591.

tert-Butyl(2′-acetamido-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9y)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9y was obtained in 91% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.32 (d, J=8.3 Hz, 1H), 8.16 (s, 1H), 7.64 (s, 1H), 7.32 (t,J=7.8 Hz, 1H), 7.25-7.17 (m, 2H), 7.14-7.07 (m, 2H), 6.94 (s, 1H), 4.89(s, 2H), 3.74 (s, 3H), 2.33 (s, 3H), 2.23 (s, 6H), 2.11 (s, 3H), 1.35(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 169.01, 163.66, 155.11, 154.76,148.93, 143.31, 139.42, 137.74, 135.06, 131.34, 129.69, 128.20, 127.12,125.19, 124.70, 124.64, 123.33, 121.30, 80.44, 59.88, 53.27, 28.12,24.53, 21.43, 13.20, 10.38; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₆N₃O₄[M+H]⁺: 490.2700, found: 490.2700.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(naphthalen-2-yl)phenyl)carbamate (9z)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9z was obtained in 76% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.19 (s, 1H), 7.92 (s, 1H), 7.89-7.81 (m, 3H), 7.63 (dd, J=8.6,1.8 Hz, 1H), 7.52-7.42 (m, 2H), 7.36 (s, 1H), 7.28 (s, 1H), 7.10 (s,1H), 4.97 (s, 2H), 3.71 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 2.22 (s,3H), 1.43 (s, 9H). ¹³C NMR (150 MHz, CDCl₃) δ 163.68, 155.22, 154.77,148.98, 143.14, 141.03, 138.48, 138.38, 133.54, 132.52, 128.17, 128.10,127.56, 126.16, 125.98, 125.78, 125.67, 125.58, 125.48, 124.67, 123.79,122.90, 80.29, 59.83, 53.57, 28.31, 21.50, 13.21, 10.47; HRMS (ESI-TOF)m/z Calcd for C₃₁H₃₅N₂O₃ [M+H]⁺: 483.2642, found: 483.2642.

tert-Butyl (3-(benzo[d][1,3]dioxol-5-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(9aa)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9aa was obtained in 72% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.13 (s, 1H), 7.06 (s, 1H), 7.03 (s, 1H),6.97-6.90 (m, 2H), 6.82 (d, J=7.8 Hz, 1H), 5.97 (s, 2H), 4.93 (s, 2H),3.72 (s, 3H), 2.32 (s, 3H), 2.22 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.66, 155.21, 154.72, 148.95, 147.88, 146.88, 142.98,140.83, 138.33, 135.44, 125.59, 124.99, 124.68, 123.79, 122.37, 120.51,108.37, 107.62, 101.03, 80.24, 59.82, 53.54, 28.29, 21.44, 13.18, 10.43;HRMS (ESI-TOF) m/z Calcd for C₂₈H₃₃N₂O₅ [M+H]⁺: 477.2384, found:477.2384.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3′,5,5′-trimethyl-[1,1′-biphenyl]-3-yl)-carbamate(9ab)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ab was obtained in 85% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.17 (s, 1H), 7.12 (s, 1H), 7.08 (s, 2H), 7.04(s, 1H), 6.94 (s, 1H), 4.94 (s, 2H), 3.71 (s, 3H), 2.34 (s, 6H), 2.32(s, 3H), 2.21 (s, 6H), 1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66,155.26, 154.79, 148.94, 142.85, 141.36, 141.04, 138.22, 137.98, 128.72,125.74, 125.32, 125.01, 124.61, 123.83, 122.72, 80.19, 59.82, 53.58,28.30, 21.44, 21.35, 13.19, 10.46; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₇N₂O₃ [M+H]⁺: 461.2799, found: 461.2799.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-methyl-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamate(9ac)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ac was obtained in 94% yield as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.89 (s, 2H), 7.81 (s, 1H), 7.28 (s, 1H), 7.19(s, 1H), 7.15 (s, 1H), 4.95 (s, 2H), 3.73 (s, 3H), 2.37 (s, 3H), 2.24(s, 3H), 2.22 (s, 3H), 1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.80,154.97, 154.60, 148.96, 143.61, 143.15, 139.22, 138.13, 131.87 (q,J=33.3 Hz), 127.42, 127.18, 125.12, 124.92, 123.84, 123.29 (q, J=273.3Hz), 122.81, 120.72, 80.64, 59.85, 53.43, 28.26, 21.43, 13.17, 10.46;¹⁹F NMR (376 MHz, CDCl₃) δ −63.09; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₁F₆N₂O₃ [M+H]⁺: 569.2233, found: 569.2233.

tert-Butyl(3′-chloro-4′-fluoro-5-methyl-[1,1′-biphenyl]-3-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(9ad)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ad was obtained in 82% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.18 (s, 1H), 7.46 (dd, J=7.0, 2.3 Hz, 1H), 7.32 (ddd, J=8.6,4.6, 2.3 Hz, 1H), 7.20-7.11 (m, 2H), 7.10 (s, 1H), 7.07 (s, 1H), 4.93(s, 2H), 3.73 (s, 3H), 2.33 (s, 3H), 2.26-2.19 (m, 6H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 163.72, 157.48 (d, J=248.7 Hz), 155.12,154.63, 148.96, 143.22, 138.91, 138.71, 138.32 (d, J=4.1 Hz), 129.14,126.70 (d, J=6.9 Hz), 126.40, 125.01, 124.77, 123.80, 122.47, 120.97 (d,J=17.8 Hz), 116.60 (d, J=21.2 Hz), 80.41, 59.86, 53.49, 28.27, 21.42,13.21, 10.45; ¹⁹F NMR (376 MHz, CDCl₃) 5-118.58; HRMS (ESI-TOF) m/zCalcd for C₂₇H₃₁ClFN₂O₃ [M+H]⁺: 485.2002, found: 485.2002.

tert-Butyl(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9ae)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ae was obtained in 82% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.12 (s, 1H), 7.08 (s, 1H), 7.01 (s, 1H),6.98-6.93 (m, 2H), 6.86 (d, J=8.7 Hz, 1H), 4.93 (s, 2H), 4.26 (s, 4H),3.72 (s, 3H), 2.31 (s, 3H), 2.21 (s, 6H), 1.41 (s, 9H); ¹³C NMR (100MHz, CDCl₃) δ 163.69, 155.18, 154.74, 148.91, 143.48, 142.99, 142.88,140.49, 138.26, 134.63, 125.54, 124.90, 124.69, 123.85, 122.27, 120.07,117.30, 115.77, 80.20, 64.40, 64.36, 59.80, 53.49, 28.29, 21.43, 13.16,10.43; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₅N₂O₅ [M+H]⁺: 491.2540, found:491.2540.

Ethyl6-(3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5-methylphenyl)-4-oxo-4H-chromene-2-carboxylate (9af)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9af was obtained in 80% yield as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.29 (d, J=2.3 Hz, 1H), 8.19 (s, 1H), 7.89 (dd, J=8.8, 2.3 Hz,1H), 7.64 (d, J=8.8 Hz, 1H), 7.34 (s, 1H), 7.23 (s, 1H), 7.17-7.10 (m,2H), 4.95 (s, 2H), 4.48 (q, J=7.1 Hz, 2H), 3.73 (s, 3H), 2.35 (s, 3H),2.24 (s, 3H), 2.23 (s, 3H), 1.45 (t, J=7.1 Hz, 3H), 1.42 (s, 9H); ¹³CNMR (150 MHz, CDCl₃) δ 178.40, 163.69, 160.49, 155.23, 155.07, 154.62,152.12, 148.96, 143.36, 138.95, 138.88, 138.83, 133.64, 126.70, 125.27,124.76, 124.40, 123.75, 123.30, 122.62, 119.08, 114.64, 80.41, 62.98,59.85, 53.44, 28.25, 21.40, 14.06, 13.19, 10.45; HRMS (ESI-TOF) m/zCalcd for C₃₃H₃₇N₂O₇ [M+H]⁺: 573.2595, found: 573.2593.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(1-tosyl-1H-indol-6-yl)phenyl)carbamate(9ag)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ag was obtained in 72% yield as a colorless solid. mp=100° C., ¹H NMR(400 MHz, CDCl₃) δ 8.24 (s, 1H), 8.12 (s, 1H), 7.76 (d, J=8.2 Hz, 2H),7.55 (d, J=3.7 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 7.35 (dd, J=8.2, 1.5 Hz,1H), 7.32 (s, 1H), 7.22-7.16 (m, 3H), 7.11 (s, 1H), 6.63 (d, J=3.6 Hz,1H), 4.98 (s, 2H), 3.71 (s, 3H), 2.37 (s, 3H), 2.32 (s, 3H), 2.24 (s,3H), 2.20 (s, 3H), 1.44 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66,155.08, 154.79, 149.03, 144.88, 143.13, 141.30, 138.39, 138.00, 135.32,135.21, 129.86, 129.81, 126.76, 126.69, 125.78, 125.46, 124.70, 123.64,122.98, 122.80, 121.26, 111.92, 108.82, 80.33, 59.83, 53.48, 28.30,21.51, 13.20, 10.42; HRMS (ESI-TOF) m/z Calcd for C₃₆H₄₀N₃O₅S [M+H]⁺:626.2683, found: 626.2683.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(1-tosyl-1H-indol-5-yl)phenyl)carbamate(9ah)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ah was obtained in 83% yield as a colorless solid. mp=92° C., ¹H NMR(400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.76 (d, J=8.1Hz, 2H), 7.60 (s, 1H), 7.55 (d, J=3.7 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H),7.27-7.19 (m, 3H), 7.13 (s, 1H), 7.05 (s, 1H), 6.65 (d, J=3.7 Hz, 1H),4.94 (s, 2H), 3.71 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H), 2.25-2.17 (m,6H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.64, 155.20, 154.71,148.92, 144.92, 143.02, 141.16, 138.35, 136.63, 135.21, 134.11, 131.12,129.86, 126.80, 126.74, 125.59, 125.39, 124.62, 124.14, 123.74, 122.76,119.72, 113.51, 109.27, 80.23, 59.81, 53.53, 28.27, 21.52, 21.44, 13.18,10.43; HRMS (ESI-TOF) m/z Calcd for C₃₆H₄₀N₃O₅S [M+H]⁺: 626.2683, found:626.2684.

tert-Butyl(3-(benzo[b]thiophen-2-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9ai)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ai was obtained in 84% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.19 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H),7.43 (s, 1H), 7.39 (s, 1H), 7.36-7.25 (m, 3H), 7.07 (s, 1H), 4.94 (s,2H), 3.72 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.43 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.69, 154.99, 154.63, 149.01, 144.10,143.25, 140.57, 139.35, 138.68, 134.09, 126.83, 124.71, 124.39, 124.38,124.17, 123.73, 123.44, 122.15, 122.08, 119.34, 80.46, 59.84, 53.35,28.29, 21.38, 13.20, 10.44; HRMS (ESI-TOF) m/z Calcd for C₂₉H₃₃N₂O₃S[M+H]⁺: 489.2206, found: 489.2206.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(5-methylthiophen-2-yl)phenyl)carbamate (9aj)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9aj was obtained in 76% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.20 (s, 1H), 7.10 (s, 1H), 6.98 (d, J=3.5 Hz,1H), 6.96 (s, 1H), 6.67 (d, J=3.5 Hz, 1H), 4.91 (s, 2H), 3.71 (s, 3H),2.47 (s, 3H), 2.28 (s, 3H), 2.21 (s, 6H), 1.42 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.64, 155.06, 154.68, 148.97, 143.09, 141.82, 139.17,138.44, 134.49, 125.98, 125.57, 124.62, 123.71, 123.48, 122.74, 121.10,80.29, 59.82, 53.38, 28.28, 21.36, 15.40, 13.18, 10.42; HRMS (ESI-TOF)m/z Calcd for C₂₆H₃₃N₂O₃S [M+H]⁺: 453.2206, found: 453.2206.

tert-Butyl(3-(5-acetylthiophen-2-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9ak)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9ak was obtained in 98% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 7.61 (d, J=3.9 Hz, 1H), 7.34 (s, 1H), 7.25-7.18(m, 2H), 7.12 (s, 1H), 4.91 (s, 2H), 3.74 (s, 3H), 2.54 (s, 3H), 2.32(s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 190.49, 163.69, 154.88, 154.50, 152.73, 148.99, 143.48, 142.79,138.92, 133.32, 133.15, 127.62, 124.78, 124.08, 123.80, 123.65, 121.75,80.52, 59.85, 53.30, 28.22, 26.47, 21.32, 13.19, 10.40; HRMS (ESI-TOF)m/z Calcd for C₂₇H₃₃N₂O₄S [M+H]⁺: 481.2156, found: 481.2156.

tert-Butyl(3-(5-formylfuran-2-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9al)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9al was obtained in 87% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 9.61 (s, 1H), 8.17 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.28(d, J=3.8 Hz, 1H), 7.14 (s, 1H), 6.74 (d, J=3.7 Hz, 1H), 4.92 (s, 2H),3.74 (s, 3H), 2.33 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.40 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 177.11, 163.71, 159.35, 154.89, 154.52,151.84, 148.94, 143.46, 139.00, 128.93, 128.53, 124.76, 123.70, 123.52,123.15, 120.87, 107.72, 80.54, 59.87, 53.29, 28.22, 21.30, 13.19, 10.44;HRMS (ESI-TOF) m/z Calcd for C₂₆H₃₁N₂O₅ [M+H]⁺: 451.2227, found:451.2227.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(1-tosyl-1H-indazol-5-yl)phenyl)carbamate(9am)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9am was obtained in 63% yield as a light yellow solid. mp=137° C., ¹HNMR (400 MHz, CDCl₃) δ 8.24-8.15 (m, 3H), 7.87 (d, J=8.2 Hz, 2H), 7.75(s, 1H), 7.69 (dd, J=8.7, 1.7 Hz, 1H), 7.29 (s, 1H), 7.25 (d, J=7.9 Hz,2H), 7.14 (s, 1H), 7.10 (s, 1H), 4.94 (s, 2H), 3.72 (s, 3H), 2.36 (s,3H), 2.34 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H); ¹³C NMR(100 MHz, CDCl₃) δ 163.67, 155.15, 154.65, 148.93, 145.37, 143.29,141.55, 140.24, 139.58, 138.64, 137.76, 134.50, 129.83, 129.12, 127.50,126.43, 126.02, 125.35, 124.68, 123.69, 122.78, 119.28, 113.20, 80.36,59.84, 53.49, 28.26, 21.60, 21.45, 13.21, 10.43; HRMS (ESI-TOF) m/zCalcd for C₃₅H₃₉N₄O₅S [M+H]⁺: 627.2636, found: 627.2635.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(1-tosyl-1H-indazol-6-yl)phenyl)carbamate(9an)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9an was obtained in 61% yield as a light yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.31 (s, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.86 (d, J=8.2 Hz,2H), 7.67 (d, J=8.3 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.41 (s, 1H),7.26-7.20 (m, 3H), 7.17 (s, 1H), 4.97 (s, 2H), 3.73 (s, 3H), 2.39 (s,3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.44 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.69, 155.02, 154.75, 149.04, 145.32, 143.40,142.70, 141.11, 140.91, 140.40, 138.71, 134.55, 129.83, 127.51, 126.63,125.66, 124.85, 124.74, 124.23, 123.62, 123.12, 121.24, 111.17, 80.46,59.86, 53.47, 28.28, 21.59, 21.48, 13.21, 10.43; HRMS (ESI-TOF) m/zCalcd for C₃₅H₃₉N₄O₅S [M+H]⁺: 627.2636, found: 627.2636.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(quinolin-3-yl)phenyl)carbamate(9ao)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ao was obtained in 54% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 9.07 (d, J=2.2 Hz, 1H), 8.21 (d, J=2.2 Hz, 1H), 8.20 (s, 1H),8.11 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.70 (t, J=7.7 Hz, 1H),7.56 (t, J=7.5 Hz, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 7.19 (s, 1H), 4.96(s, 2H), 3.73 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.42(s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.69, 155.04, 154.67, 149.94,149.02, 147.26, 143.64, 138.96, 137.79, 133.70, 133.14, 129.25, 129.16,127.94, 126.89, 126.62, 125.32, 124.74, 123.63, 122.75, 80.48, 59.86,53.49, 28.29, 21.50, 13.22, 10.43; HRMS (ESI-TOF) m/z Calcd forC₃₀H₃₄N₃O₃ [M+H]⁺: 484.2595, found: 484.2593.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(quinolin-6-yl)phenyl)carbamate(9ap)

Following the general meta-arylation procedure using 20 mol % ofPd(OAc)₂ and 40 mol % of L12, Compound 9ap was obtained in 41% yield asa light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.90 (dd, J=4.3, 1.7Hz, 1H), 8.22-8.16 (m, 2H), 8.12 (d, J=8.7 Hz, 1H), 7.91 (d, J=2.0 Hz,1H), 7.87 (dd, J=8.7, 2.1 Hz, 1H), 7.41 (dd, J=8.3, 4.2 Hz, 1H), 7.39(s, 1H), 7.28 (s, 1H), 7.13 (s, 1H), 4.97 (s, 2H), 3.73 (s, 3H), 2.38(s, 3H), 2.24 (s, 3H), 2.22 (s, 3H), 1.43 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 163.72, 155.18, 154.72, 150.25, 148.98, 147.60, 143.29, 140.25,139.18, 138.68, 136.20, 129.65, 129.25, 128.36, 126.37, 125.51, 125.39,124.73, 123.81, 122.94, 121.39, 80.40, 59.86, 53.54, 28.31, 21.50,13.22, 10.47; HRMS (ESI-TOF) m/z Calcd for C₃₀H₃₄N₃O₃ [M+H]⁺: 484.2595,found: 484.2592.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(quinoxalin-6-yl)phenyl)carbamate(9aq)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9aq was obtained in 63% yield as a yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.85 (d, J=1.8 Hz, 1H), 8.82 (d, J=1.8 Hz, 1H), 8.19 (s, 2H),8.13 (d, J=8.7 Hz, 1H), 7.96 (dd, J=8.8, 2.0 Hz, 1H), 7.44 (s, 1H), 7.32(s, 1H), 7.19 (s, 1H), 4.97 (s, 2H), 3.74 (s, 3H), 2.39 (s, 3H), 2.25(s, 3H), 2.23 (s, 3H), 1.42 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.71,155.09, 154.66, 149.01, 145.30, 144.62, 143.47, 143.17, 142.77, 142.29,139.51, 138.86, 129.87, 129.58, 126.94, 126.75, 125.58, 124.78, 123.75,122.97, 80.44, 59.86, 53.49, 28.28, 21.49; HRMS (ESI-TOF) m/z Calcd forC₂₉H₃₃N₄O₃ [M+H]⁺: 485.2547, found: 485.2547.

tert-Butyl(3-(2-fluoropyridin-4-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9ar)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ar was obtained in 90% yield as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.20 (d, J=5.3 Hz, 1H), 8.18 (s, 1H), 7.33 (s, 1H), 7.30 (d,J=5.2 Hz, 1H), 7.21 (s, 1H), 7.18 (s, 1H), 7.00 (s, 1H), 4.93 (s, 2H),3.74 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 164.36 (d, J=237.8 Hz), 163.74, 154.94,154.52, 153.98, 153.93, 148.96, 147.74 (d, J=15.4 Hz), 143.61, 139.11,136.99, 128.18, 124.87, 123.74, 122.46, 119.49 (d, J=3.9 Hz), 107.00 (d,J=38.3 Hz), 80.59, 59.86, 53.35, 28.23, 21.40, 13.20, 10.42; ¹⁹F NMR(376 MHz, CDCl₃) δ −68.68; HRMS (ESI-TOF) m/z Calcd for C₂₆H₃₁FN₃O₃[M+H]⁺: 452.2344, found: 452.2344.

tert-Butyl(3-(2-chloropyridin-4-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9as)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9as was obtained in 96% yield as a colorless liquid. Only 9% NMR yieldwas obtained in the absence of L12. ¹H NMR (400 MHz, CDCl₃) δ 8.37 (d,J=5.2 Hz, 1H), 8.18 (s, 1H), 7.41 (s, 1H), 7.33 (dd, J=5.2, 1.5 Hz, 1H),7.30 (s, 1H), 7.21 (s, 1H), 7.16 (s, 1H), 4.93 (s, 2H), 3.74 (s, 3H),2.36 (s, 3H), 2.24 (s, 6H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ163.74, 154.94, 154.50, 151.97, 151.44, 149.79, 148.96, 143.62, 1.3.1b,136.76, 128.20, 124.87, 124.84, 123.74, 122.47, 121.97, 120.46, 80.59,59.87, 53.36, 28.22, 21.39, 13.21, 10.42; HRMS (ESI-TOF) m/z Calcd forC₂₆H₃₁ClN₃O₃ [M+H]⁺: 468.2048, found: 468.2048.

tert-Butyl(3-(2-bromopyridin-4-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9at)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9at was obtained in 56% yield as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.35 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.57 (s, 1H), 7.36 (dd,J=5.2, 1.5 Hz, 1H), 7.29 (s, 1H), 7.20 (s, 1H), 7.15 (s, 1H), 4.93 (s,2H), 3.74 (s, 3H), 2.36 (s, 3H), 2.23 (s, 6H), 1.41 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.77, 154.92, 154.51, 151.18, 150.19, 148.95,143.60, 142.70, 139.17, 136.64, 128.22, 125.78, 124.90, 124.88, 123.78,122.49, 120.84, 80.62, 59.89, 53.34, 28.24, 21.40, 13.24, 10.44; HRMS(ESI-TOF) m/z Calcd for C₂₆H₃₁BrN₃O₃ [M+H]⁺: 512.1543, found: 512.1540.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(2-(trifluoromethyl)pyridin-4-yl)-phenyl)-carbamate (9au)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9au was obtained in 93% yield as a light yellow liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.72 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.77 (s, 1H), 7.60 (d,J=3.5 Hz, 1H), 7.39 (s, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 4.94 (s, 2H),3.74 (s, 3H), 2.38 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 1.41 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 163.76, 154.90, 154.52, 150.27, 150.10,148.96, 149.49 (q, J=33.2 Hz), 143.80, 139.32, 136.79, 128.33, 124.88,124.86, 124.10, 123.73, 122.54, 121.61 (q, J=274.4 Hz), 118.40 (q, J=3.0Hz), 80.67, 59.86, 53.34, 28.23, 21.41, 13.18, 10.42; ¹⁹F NMR (376 MHz,CDCl₃) δ −68.23; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₁F₃N₃O₃ [M+H]⁺:502.2312, found: 502.2312.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(2-methylpyridin-4-yl)phenyl)carbamate (9av)

Following the general meta-arylation procedure using 20 mol % ofPd(OAc)₂ and 40 mol % of L12, Compound 9av was obtained in 42% yield asa colorless, liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.48 (d, J=5.2 Hz, 1H),8.18 (s, 1H), 7.31 (s, 1H), 7.26 (s, 1H), 7.20 (d, J=5.2 Hz, 1H), 7.17(s, 1H), 7.16 (s, 1H), 4.93 (s, 2H), 3.73 (s, 3H), 2.59 (s, 3H), 2.35(s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 163.69, 158.62, 155.06, 154.60, 149.38, 148.95, 148.54, 143.40,138.81, 138.38, 127.42, 124.93, 124.73, 123.72, 122.47, 121.15, 118.82,80.44, 59.84, 53.44, 28.26, 24.52, 21.42, 13.20, 10.43; HRMS (ESI-TOF)m/z Calcd for C₂₇H₃₄N₃O₃ [M+H]⁺: 448.2595, found: 448.2596.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-(2-methoxypyridin-4-yl)-5-methylphenyl)carbamate(9aw)

Following the general meta-acylation procedure using NBE-CO₂Me, Compound9aw was obtained in 55% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 8.15 (d, J=5.4 Hz, 1H), 7.26 (s, 1H), 7.16 (s,2H), 7.00 (dd, J=5.4, 1.5 Hz, 1H), 6.81 (s, 1H), 4.93 (s, 2H), 3.96 (s,3H), 3.73 (s, 3H), 2.34 (s, 3H), 2.22 (s, 6H), 1.41 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 164.75, 163.73, 155.03, 154.61, 151.08, 148.97,147.00, 143.32, 138.77, 138.21, 127.54, 124.94, 124.80, 123.77, 122.46,115.38, 108.37, 80.46, 59.84, 53.46, 53.43, 28.26, 21.42, 13.20, 10.43;HRMS (ESI-TOF) m/z Calcd for C²⁷H³⁴N³O⁴ [M+H]⁺: 464.2544, found:464.2544.

Methyl4-(3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5-methyl-phenyl)-2-chloronicotinate(9ax)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ax was obtained in 51% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.41 (d, J=5.1 Hz, 1H), 8.18 (s, 1H), 7.24-7.19 (m, 2H), 7.17(s, 1H), 6.96 (s, 1H), 4.88 (s, 2H), 3.74 (s, 3H), 3.70 (s, 3H), 2.32(s, 3H), 2.225 (s, 3H), 2.217 (s, 3H), 1.37 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 166.19, 163.68, 154.86, 154.45, 150.21, 149.72, 148.97, 147.93,143.57, 138.86, 136.58, 128.83, 127.89, 125.55, 124.74, 123.48, 123.09,123.05, 80.52, 59.88, 53.32, 52.70, 28.18, 21.36, 13.22, 10.37; HRMS(ESI-TOF) m/z Calcd for C₂₈H₃₃ClN₃O₅ [M+H]⁺: 526.2103, found: 526.2103.

tert-Butyl(3-(6-fluoropyridin-3-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9ay)

Following the general meta-arylation procedure using NBE-CO₂Me, Compound9ay was obtained in 52% yield as a colorless liquid. ¹H NMR (400 MHz,CDCl₃) δ 8.30 (d, J=2.6 Hz, 1H), 8.17 (s, 1H), 7.88 (td, J=8.0, 2.6 Hz,1H), 7.26 (s, 1H), 7.15 (s, 1H), 7.08 (s, 1H), 6.95 (dd, J=8.5, 3.0 Hz,1H), 4.93 (s, 2H), 3.73 (s, 3H), 2.35 (s, 3H), 2.26-2.20 (m, 6H), 1.40(s, 9H); ¹³C NMR (126 MHz, CDCl₃) δ 163.70, 162.98 (d, J=238.4 Hz),155.02, 154.60, 148.97, 145.74 (d, J=14.9 Hz), 143.59, 139.68 (d, J=7.8Hz), 138.95, 136.60, 134.70 (d, J=4.6 Hz), 126.67, 124.93, 124.75,123.64, 122.41, 109.22 (d, J=37.5 Hz), 80.48, 59.85, 53.44, 28.25,21.42, 13.20, 10.41; ¹⁹F NMR (376 MHz, CDCl₃) δ −71.02; HRMS (ESI-TOF)m/z Calcd for C₂₆H₃₁FN₃O₃ [M+H]⁺: 452.2344, found: 452.2344.

tert-Butyl(3-(6-chloropyridin-3-yl)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9az)

Following the general meta-arylation procedure using NEE-CO₂Me, Compound9az was obtained in 52% yield as a colorless solid. ¹H NMR (400 MHz,CDCl₃) δ 8.49 (d, J=2.5 Hz, 1H), 8.17 (s, 1H), 7.75 (dd, J=8.2, 2.6 Hz,1H), 7.34 (d, J=8.3 Hz, 1H), 7.28 (s, 1H), 7.16 (s, 1H), 7.09 (s, 1H),4.92 (s, 2H), 3.73 (s, 3H), 2.35 (s, 3H), 2.22 (s, 6H), 1.40 (s, 9H);¹³C NMR (150 MHz, CDCl₃) δ 163.70, 154.96, 154.59, 150.12, 148.98,147.93, 143.68, 139.05, 137.15, 136.39, 135.51, 126.93, 124.87, 124.77,124.04, 123.64, 122.34, 80.54, 59.87, 53.41, 28.24, 21.43, 13.21, 10.40;HRMS (ESI-TOF) m/z Calcd for C₂₆H₃₁ClN₃O₃ [M+H]⁺: 468.2048, found:468.2048.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-(3-methyl-5-(6-(trifluoromethyl)pyridin-2-yl)-phenyl)carbamate(9ba)

Following the general meta-arylation procedure using 20 mol % ofPd(OAc)₂ and 40 mol % of L12, Compound 9ba was obtained in 84% yield asa red liquid. ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 1H), 7.86 (t, J=7.8 Hz,1H), 7.80 (d, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.62 (s, 1H), 7.56 (d, J=7.5Hz, 1H), 7.18 (s, 1H), 4.97 (s, 2H), 3.71 (s, 3H), 2.36 (s, 3H), 2.24(s, 3H), 2.20 (s, 3H), 1.43 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.77,157.56, 154.95, 154.71, 148.86, 147.93 (q, J=34.2 Hz), 143.17, 138.72,137.86, 137.73, 128.28, 124.93, 124.76, 123.89, 122.84, 122.68, 121.51(q, J=274.5 Hz), 118.35 (q, J=2.8 Hz), 80.50, 59.82, 53.25, 28.23,21.45, 13.16, 10.44; HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₁F₃N₃O₃ [M+H]⁺:502.2312, found: 502.2312.

tert-Butyl(2′-chloro-6-methoxy-[4,4′-bipyridin]-2-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9bb)

Substrate 2b was arylated following the general meta-arylation procedureusing 20 mol % of Pd(OAc)₂ and 40 mol % of L12. After purification bypreparative thin-layer chromatography, Compound 9bb was obtained in 40%yield as a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ 8.44 (d, J=5.2 Hz,1H), 8.12 (s, 1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.44 (dd, J=5.2, 1.5 Hz,1H), 6.55 (s, 1H), 5.26 (s, 2H), 3.74 (s, 3H), 3.65 (s, 3H), 2.27 (s,3H), 2.21 (s, 3H), 1.45 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.38,162.79, 155.60, 154.34, 153.17, 152.24, 150.12, 149.73, 148.92, 148.15,123.97, 122.26, 122.23, 120.60, 108.40, 102.43, 81.45, 59.88, 53.22,48.92, 28.16, 13.17, 10.34; HRMS (ESI-TOF) m/z Calcd for C₂₅H₃₀ClN₄O₄[M+H]⁺: 485.1950, found: 485.1950.

tert-Butyl4-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-6-(2-chloro-pyridin-4-yl)-1H-indole-1-carboxylate(9bc)

Substrate 2i was arylated following the general meta-arylation procedureusing 20 mol % of Pd(OAc)₂ and 40 mol % of L12. After purification bypreparative thin-layer chromatography, Compound 9bc was obtained in 48%yield as a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ 8.41-8.31 (m, 2H),8.13 (s, 1H), 7.61 (d, J=3.7 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J=5.2 Hz,1H), 7.21 (s, 1H), 6.58 (d, J=3.7 Hz, 1H), 5.02 (s, 2H), 3.71 (s, 3H),2.23 (s, 3H), 2.22 (s, 3H), 1.68 (s, 9H), 1.37 (s, 9H); ¹³C NMR (150MHz, CDCl₃) δ 163.83, 154.94, 154.56, 152.00, 151.86, 149.75, 149.35,148.90, 136.46, 135.52, 132.83, 129.57, 127.15, 125.08, 124.60, 121.95,120.53, 112.49, 105.52, 84.22, 80.54, 59.82, 53.19, 28.18, 28.12, 13.21,10.62; HRMS (ESI-TOF) m/z Calcd for C₃₂H₃₈ClN₄O₅ [M+H]⁺: 593.2525,found: 593.2522.

tert-Butyl(8-(2-chloropyridin-4-yl)-2,3-dihydrobenzo[b]-[1,4]dioxin-6-yl)((4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl)carbamate(9bd)

Substrate 2l was arylated following the general meta-arylationprocedure. After purification by preparative thin-layer chromatography,Compound 9bd was obtained in 52% yield as a colorless solid. ¹H NMR (400MHz, CDCl₃) δ 8.35 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 7.39 (s, 1H), 7.32(d, J=5.2 Hz, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 4.86 (s, 2H), 4.24 (s,4H), 3.74 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 1.40 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.78, 154.92, 154.72, 151.27, 149.10, 148.92,148.27, 143.53, 138.83, 136.28, 125.60, 124.89, 124.36, 123.90, 122.86,121.00, 117.09, 80.50, 64.34, 63.99, 59.88, 53.56, 28.25, 13.23, 10.43;HRMS (ESI-TOF) m/z Calcd for C₂₇H₃₁ClN₃O₅ [M+H]⁺: 512.1947, found:512.1948.

tert-Butyl(4-(2-chloropyridin-4-yl)thiophen-2-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9be)

Substrate 2c was arylated following the general meta-arylationprocedure. After purification by preparative thin-layer chromatography,Compound 9be was obtained in 93% yield as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.30 (d, J=5.2 Hz, 1H), 8.20 (s, 1H), 7.36 (s, 1H),7.29-7.22 (m, 2H), 6.92 (s, 1H), 5.03 (s, 2H), 3.75 (s, 3H), 2.23 (s,6H), 1.48 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.86, 153.64, 153.46,152.08, 149.83, 149.05, 146.81, 145.94, 134.60, 125.14, 123.73, 120.55,119.14, 118.02, 112.98, 82.30, 59.91, 53.42, 28.12, 13.23, 10.29; HRMS(ESI-TOF) m/z Calcd for C₂₃H₂₇ClN₃O₃S [M+H]⁺: 460.1456, found: 460.1456.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(4-(2-(trifluoromethyl)pyridin-4-yl)thiophen-2-yl)carbamate(9bf)

Substrate 2c was arylated following the general meta-arylationprocedure. After purification by preparative thin-layer chromatography,Compound 9bf was obtained in 80% yield as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.64 (d, J=5.2 Hz, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 7.52(d, J=5.0 Hz, 1H), 7.31 (s, 1H), 6.99 (s, 1H), 5.05 (s, 2H), 3.75 (s,3H), 2.27-2.20 (m, 6H), 1.49 (s, 9H); ¹⁹C NMR (150 MHz, CDCl₃) δ 163.92,153.69, 153.46, 150.38, 149.08, 148.72 (q, J=34.7 Hz), 147.03, 144.65,134.71, 125.22, 123.81, 122.65, 121.60 (q, J=274.3 Hz), 118.52, 117.08(d, J=3.4 Hz), 112.86, 82.42, 59.93, 53.44, 28.15, 13.24, 10.32; ¹⁹F NMR(376 MHz, CDCl₃) δ −68.37; HRMS (ESI-TOF) m/z Calcd for C₂₄H₂₇F₃N₃O₃S[M+H]⁺: 494.1720, found: 494.1718.

tert-Butyl(5-acetyl-[2,3′-bithiophen]-5′-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(9bg)

Substrate 2c was arylated following the general meta-arylationprocedure. After purification by preparative thin-layer chromatography,Compound 9bg was obtained in 47% yield as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.19 (s, 1H), 7.56 (d, J=3.9 Hz, 1H), 7.11 (s, 1H), 7.07(d, J=3.9 Hz, 1H), 6.83 (s, 1H), 5.00 (s, 2H), 3.75 (s, 3H), 2.52 (s,3H), 2.23 (s, 6H), 1.48 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 190.47,163.83, 153.61, 153.55, 149.12, 148.08, 146.41, 141.70, 133.34, 131.48,125.08, 123.66, 123.36, 116.57, 113.35, 82.24, 59.94, 53.39, 28.15,26.45, 13.24, 10.29; HRMS (ESI-TOF) m/z Calcd for C₂₄H₂₉N₂O₄S₂ [M+H]⁺:473.1563, found: 473.1564.

Ethyl6-(5-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)thiophen-3-yl)-4-oxo-4H-chromene-2-carboxylate(9bh)

Substrate 2c was arylated following the general meta-arylationprocedure. After purification by preparative thin-layer chromatography,Compound 9bh was obtained in 41% yield as a yellow solid. ¹H NMR (400MHz, CDCl₃) δ 8.25-8.18 (m, 2H), 7.87 (dd, J=8.8, 2.3 Hz, 1H), 7.59 (d,J=8.8 Hz, 1H), 7.14 (s, 1H), 7.10 (s, 1H), 6.98 (s, 1H), 5.03 (s, 2H),4.47 (q, J=7.2 Hz, 2H), 3.76 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H), 1.47(s, 9H), 1.44 (t, J=7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 178.43,163.81, 160.49, 154.87, 153.82, 153.65, 152.09, 149.13, 146.50, 136.66,134.12, 132.60, 125.02, 124.46, 123.63, 121.85, 119.12, 115.84, 114.55,113.82, 82.02, 62.98, 59.93, 53.55, 28.16, 14.07, 13.23, 10.33; HRMS(ESI-TOF) m/z Calcd for C₃₀H₃₃N₂O₇S [M+H]⁺: 565.2003, found: 565.2002.

Meta-Arylation of Lenalidomide Derivative

General Procedures for meta-Arylation of Lenalidomide:

Substrate (0.05 mmol), Ar—I (0.1 mmol), Pd(OAc)₂ (1.1 mg, 10 mol %), L12(1.5 mg, 20 mol %), AgOAc (25.0 mg, 0.15 mmol), NBE-CO₂Me (11.4 mg,0.075 mmol) and DCE (0.5 mL) were added to a 2-dram vial. The vial wascapped and closed tightly. The reaction mixture was then stirred at 100°C. for 24 hours. After cooling to room temperature, the mixture waspassed through a pad of Celite® with DCM as the eluent to remove theinsoluble precipitate. The resulting solution was concentrated andpurified by preparative TLC plate to afford the desired arylated productin 61% yield as a colorless solid.

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 8.15 (s, 1H),7.85 (d, J=7.7 Hz, 1H), 7.71 (s, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.43 (t,J=7.6 Hz, 1H), 7.33 (d, =5.7 Hz, 1H), 5.25 (dd, J=13.3, 5.1 Hz, 1H),4.89 (s, 2H), 4.66 (d, J=16.5 Hz, 1H), 4.51 (d, J=16.5 Hz, 1H), 3.71 (s,3H), 3.58 (s, 3H), 3.00-2.78 (m, 2H), 2.38 (qd, J=13.6, 13.0, 4.7 Hz,1H), 2.29-2.14 (m, 7H), 1.36 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 170.70,168.99, 168.46, 168.02, 163.38, 153.82, 153.25, 148.36, 142.11, 140.57,138.02, 137.33, 131.90, 131.07, 130.42, 130.15, 130.07, 129.73, 127.24,124.61, 121.49, 80.50, 59.45, 52.42, 51.43, 51.35, 45.99, 31.15, 27.72,23.05, 12.80, 9.95; HRMS (ESI-TOF) m/z Calcd for C₃₅H₃₉N₄O₈ [M+H]⁺:643.2762, found: 643.2762.

3.15 Meta-Arylation of Anilines without Sliver

General Procedure for Arylation of 1a without Sliver Using Methyl2-iodobenzoate as Coupling Partner on Gram Scale:

Substrate 1a (35.6 mg, 0.1 mmol), methyl 2-iodobenzoate (30 μL, 0.2mmol), Pd(OAc)₂ (1.2 mg, 5 mol %), L12 (1.5 mg, 10 mol %), CsOAc (57.6mg, 0.3 mmol), NBE-CO₂Me (21.6 mg, 0.15 mmol), and t-Amyl-OH (0.2 mL)were added to a 2-dram vial. The vial was capped and closed tightly.Then the reaction mixture was stirred at 100° C. for 24 hours. Aftercooling to room temperature, the mixture was passed through a pad ofCelite® with DCM as the eluent to remove the insoluble precipitate. Theresulting solution was concentrated and purified by preparative TLC toafford the desired product Compound 5a in 82% yield.

General Procedure for Arylation of 1a without Sliver Using Iodobenzeneas Coupling Partner:

Substrate 1a (35.6 mg, 0.1 mmol), iodobenzene (23 μL, 0.2 mmol),Pd(OAc)₂ (1.2 mg, 5 mol %), L17 (1.5 mg, 10 mol %), CsOAc (57.6 mg, 0.3mmol), NBE-CO₂Me (21.6 mg, 0.15 mmol), and t-Amyl-OH (0.2 mL) were addedto a 2-dram vial. The vial was capped and closed tightly. Then thereaction mixture was stirred at 100° C. for 15 hours. After cooling toroom temperature, the mixture was diluted by DCM (5.0 mL) and stirredfor 10 minutes. The mixture was passed through a pad of Celite® with DCMas the eluent to remove the insoluble precipitate. After concentration,CsOAc (57.6 mg, 0.3 mmol), Pd(OAc)₂ (1.2 mg, 5 mol %) and t-Amyl-OH (0.2mL) were added into a 2-dram vial with the residue. The vial was cappedand closed tightly, the reaction mixture was then stirred at 100° C. foranother 16 hours. After cooling to room temperature, the mixture waspassed through a pad of Celite® with DCM as the eluent to remove theinsoluble precipitate. The resulting solution was concentrated andpurified by preparative TLC to afford the desired product Compound 9a in73% yield.

Meta-Amination of Anilines

General Procedure for Amination of Anilines:

Substrate 1 or 2 (0.1 mmol), aminating reagent (0.15 mmol), Pd(OAc)₂(2.2 mg, 10 mol %), L24 (3.4 mg, 10 mol %), AgOAc (33.4 mg, 0.2 mmol),NBE-CO₂Me (21.6 mg, 0.15 mmol), K₃PO₄ (62.8 mg, 0.3 mmol) and DCM (1.0mL) were added to a 2-dram vial. The vial was capped and closed tightly.Then the reaction mixture was then stirred at 100° C. for 24 hours.After cooling to room temperature, the mixture was passed through a padof Celite® with DCM as the eluent to remove the insoluble precipitate.The resulting solution was concentrated and purified by preparative TLCto afford the desired product Compound 10.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-morpholinophenyl)carbamate(10a)

Substrate 1a was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10a was obtained in 77% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.16 (s, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.49 (s,1H), 4.87 (s, 2H), 3.80 (t, J=4.8 Hz, 4H), 3.72 (s, 3H), 3.04 (t, J=4.8Hz, 4H), 2.23 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.39 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.59, 155.36, 154.75, 151.28, 148.87, 143.53,138.55, 124.54, 123.72, 119.03, 114.16, 111.84, 80.06, 66.90, 59.81,53.60, 49.52, 28.29, 21.72, 13.19, 10.42; HRMS (ESI-TOF) m/z Calcd forC₂₅H₃₆N₃O₄ [M+H]⁺: 442.2700, found: 442.2700.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methoxy-5-morpholinophenyl)carbamate(10b)

Substrate 1b was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10b was obtained in 65% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.16 (s, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 6.22 (t,J=2.2 Hz, 1H), 4.88 (s, 2H), 3.80 (t, J=4.7 Hz, 4H), 3.72 (s, 3H), 3.70(s, 3H), 3.05 (t, J=4.6 Hz, 4H), 2.21 (s, 3H), 2.20 (s, 3H), 1.40 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.57, 160.15, 155.20, 154.64, 152.11,148.88, 144.47, 124.57, 123.70, 107.47, 103.88, 99.79, 80.17, 66.81,59.82, 55.20, 53.57, 49.31, 28.29, 13.19, 10.41; HRMS (ESI-TOF) m/zCalcd for C₂₅H₃₆N₃O₅ [M+H]⁺: 458.2649, found: 458.2650.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-(methylthio)-5-morpholinophenyl)-carbamate (10c)

Substrate 1c was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10c was obtained in 57% yield as a colorless solid, ¹H NMR (400MHz, CDCl₃) δ 8.16 (s, 1H), 6.67 (s, 1H), 6.65 (s, 1H), 6.57 (t, J=2.0Hz, 1H), 4.87 (s, 2H), 3.84-3.76 (m, 4H), 3.72 (s, 3H), 3.10-3.01 (m,4H), 2.38 (s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.40 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.63, 155.09, 154.59, 151.51, 148.89, 144.05,138.70, 124.67, 123.76, 116.61, 111.87, 111.62, 80.31, 66.79, 59.85,53.43, 49.24, 28.29, 16.01, 13.20, 10.43; HRMS (ESI-TOF) m/z Calcd forC₂₅H₃₆N₃O₄S [M+H]⁺: 474.2421, found: 474.2421.

tert-Butyl(3-fluoro-5-morpholinophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(10d)

Substrate 1e was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10d was obtained in 63% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.16 (s, 1H), 6.65 (s, 1H), 6.51 (dt, J=10.0, 2.1 Hz,1H), 6.35 (dt, J=11.7, 2.3 Hz, 1H), 4.86 (s, 2H), 3.84-3.77 (m, 4H),3.73 (s, 3H), 3.10-3.03 (m, 4H), 2.22 (s, 3H), 2.20 (s, 3H), 1.39 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 164.00, 163.65, 162.40, 154.84, 152.24,152.16, 148.93, 144.78, 144.69, 124.72, 123.61, 109.47, 105.05, 104.89,99.91, 99.74, 80.54, 66.64, 59.85, 53.35, 28.21, 13.20, 10.37; HRMS(ESI-TOF) m/z Calcd for C₂₄H₃₃FN₃O₄ [M+H]⁺: 446.2450, found: 446.2452.

tert-Butyl(3-chloro-5-morpholinophenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(10e)

Substrate 1f was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10e was obtained in 63% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.17 (s, 1H), 6.77 (s, 2H), 6.63 (t, J=2.1 Hz, 1H),4.85 (s, 2H), 3.84-3.77 (m, 4H), 3.73 (s, 3H), 3.10-3.02 (m, 4H), 2.22(s, 3H), 2.20 (s, 3H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.66,154.80, 154.35, 151.92, 148.94, 144.54, 134.17, 124.75, 123.62, 117.94,112.84, 112.50, 80.58, 66.66, 59.86, 53.30, 48.87, 28.22, 13.21, 10.39;HRMS (ESI-TOF) m/z Calcd for C₂₄H₃₃ClN₃O₄ [M+H]⁺: 462.2154, found:462.2155.

Methyl3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5-morpholino-benzoate(10f)

Substrate 1h was aminated following the general meta-amination procedureusing Pd(OAc)₂ (3.4 mg, 15 mol %), L24 (5.1 mg, 15 mol %), AgOAc (50.1mg, 0.3 mmol) and NBE-CO₂Me (45.7 mg, 0.3 mmol). After purification bypreparative thin-layer chromatography, Compound 10f was obtained in 60%yield as a colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H), 7.42(s, 1H), 7.36-7.32 (m, 1H), 7.08 (s, 1H), 4.91 (s, 2H), 3.86 (s, 3H),3.84-3.80 (m, 4H), 3.72 (s, 3H), 3.15-3.08 (m, 4H), 2.23-2.19 (m, 6H),1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 166.97, 163.71, 154.89, 154.48,151.26, 148.90, 143.71, 130.80, 124.78, 123.86, 119.26, 118.86, 113.76,80.55, 66.74, 59.85, 53.24, 52.09, 49.06, 28.23, 13.21, 10.46; HRMS(ESI-TOF) m/z Calcd for C₂₆H₃₆N₃O₆ [M+H]⁺: 486.2599, found: 486.2600.

tert-Butyl(1-acetyl-4-morpholinoindolin-6-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(10g)

Substrate 2g was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10g was obtained in 76% yield as a light yellow solid,Rotameric mixture, ratio of the rotamers=74/26; ¹H NMR (500 MHz, CDCl₃)δ 8.14 (s, 1H), 7.87 (s, 0.74H), 6.86 (s, 0.26H), 6.68-6.52 (m, 1H),4.97-4.81 (m, 2H), 4.09 (t, J=8.4 Hz, 0.52H), 4.01 (t, J=8.2 Hz, 1.48H),3.84-3.76 (m, 4H), 3.76-3.69 (m, 3H), 3.02 (t, J=8.3 Hz, 1.42H),2.97-2.82 (m, 4.52H), 2.28-2.13 (m, 9H), 1.41 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) resonances for the minor rotamer are enclosed in parenthesis ( ):δ 168.21, 163.64 (163.71), 155.27 (155.13), 154.74, 148.77 (148.88),147.80, 143.81, 143.21 (142.78), 124.56 (124.83), 123.96 (123.43),120.93, 112.74 (111.75), 110.80 (108.80), 80.22 (80.41), 67.15 (67.10),59.82, 53.53 (53.68), 50.91 (50.71), 49.41 (48.60), 28.29, 26.61(25.61), 24.21 (24.00), 13.18, 10.48 (10.45); HRMS (ESI-TOF) m/z Calcdfor C₂₈H₃₉N₄O₅ [M+H]⁺: 511.2915, found: 511.2914.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(1-methyl-4-morpholino-1H-indazol-6-yl)-carbamate (10h)

Substrate 2j was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10h was obtained in 62% yield as a colorless solid, ¹H NMR (400MHz, CDCl₃) δ 8.16 (s, 1H), 7.86-7.79 (m, 2H), 6.93 (s, 1H), 6.44 (s,1H), 4.95 (s, 2H), 3.94 (s, 3H), 3.92-3.88 (m, 4H), 3.73 (s, 3H),3.25-3.16 (m, 4H), 2.23 (s, 3H), 2.22 (s, 3H), 1.41 (s, 9H); ¹³C NMR(150 MHz, CDCl₃) δ 163.67, 155.14, 154.75, 148.88, 145.25, 142.42,141.34, 130.99, 124.73, 123.82, 115.44, 106.64, 100.31, 80.40, 66.89,59.83, 53.94, 51.40, 35.64, 28.29, 13.21, 10.48; HRMS (ESI-TOF) m/zCalcd for C₂₆H₃₆N₅O₄ [M+H]⁺: 482.2762, found: 482.2766.

tert-Butyl6-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-4-morpholino-1H-indole-1-carboxylate(10i)

Substrate 2h was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10i was obtained in 53% yield as a colorless solid, ¹H NMR (400MHz, CDCl₃) δ 8.12 (s, 1H), 7.67 (s, 1H), 7.49 (d, J=3.7 Hz, 1H), 6.66(s, 1H), 6.48 (d, J=3.7 Hz, 1H), 4.97 (s, 2H), 3.89 (t, J=4.5 Hz, 4H),3.72 (s, 3H), 3.06 (t, J=4.6 Hz, 4H), 2.23 (s, 3H), 2.20 (s, 3H), 1.57(s, 9H), 1.41 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.67, 155.32,154.97, 149.52, 148.85, 144.70, 140.07, 135.82, 124.76, 124.63, 124.02,121.87, 110.77, 108.56, 105.03, 83.54, 80.10, 67.12, 59.78, 54.13,52.06, 28.34, 28.02, 28.01, 13.15, 10.50; HRMS (ESI-TOF) m/z Calcd forC₃₁H₄₃N₄O₆ [M+H]⁺: 567.3177, found: 567.3179.

tert-Butyl4-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-6-morpholino-1H-indole-1-carboxylate(10j)

Substrate 2i was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10j was obtained in 44% yield as a colorless solid, ¹H NMR (400MHz, CDCl₃) δ 8.11 (s, 1H), 7.60 (s, 1H), 7.38 (d, J=3.7 Hz, 1H), 6.69(s, 1H), 6.41 (d, J=3.8 Hz, 1H), 4.95 (s, 2H), 3.86-3.78 (m, 4H), 3.68(s, 3H), 3.12-3.01 (m, 4H), 2.23-2.13 (m, 6H), 1.64 (s, 9H), 1.35 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.63, 155.23, 154.80, 149.81, 149.28,148.83, 136.84, 135.05, 124.71, 124.42, 124.05, 122.23, 112.58, 105.50,101.10, 83.29, 80.10, 66.95, 59.75, 53.28, 50.54, 28.22, 28.17, 13.16,10.57; HRMS (ESI-TOF) m/z Calcd for C₃₁H₄₃N₄O₆ [M+H]⁺: 567.3177, found:567.3174.

tert-Butyl(3-(2,6-dimethylmorpholino)-5-methylphenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(10k)

Substrate 1a was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10k was obtained in 81% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.15 (s, 1H), 6.57 (s, 2H), 6.48 (s, 1H), 4.87 (s,2H), 3.80-3.67 (m, 5H), 3.30 (d, J=10.4 Hz, 2H), 2.31 (t, J=11.1 Hz,2H), 2.25-2.18 (m, 9H), 1.39 (s, 9H), 1.23 (s, 3H), 1.21 (s, 3H); ¹³CNMR (150 MHz, CDCl₃) δ 163.58, 155.40, 154.76, 150.94, 148.83, 143.42,138.55, 124.52, 123.79, 118.79, 114.24, 112.01, 80.02, 71.55, 59.81,54.99, 53.62, 28.28, 21.71, 19.01, 13.18, 10.43; HRMS (ESI-TOF) m/zCalcd for C₂₇H₄₀N₃O₄ [M+H]⁺: 470.3013, found: 470.3014.

tert-Butyl4-(3-((tert-butoxycarbonyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-5-methylphenyl)piperazine-1-carboxylate(10l)

Substrate 1a was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10l was obtained in 84% yield as a colorless solid, ¹H NMR (400MHz, CDCl₃) δ 8.15 (s, 1H), 6.63 (s, 1H), 6.61 (s, 1H), 6.50 (s, 1H),4.87 (s, 2H), 3.72 (s, 3H), 3.52 (t, J=5.1 Hz, 4H), 3.01 (t, J=5.2 Hz,4H), 2.23 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.48 (s, 9H), 1.39 (s,9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.56, 155.30, 154.67, 151.23, 148.85,143.46, 138.54, 124.54, 123.68, 119.20, 115.09, 112.60, 80.06, 79.78,59.80, 53.57, 49.53, 44.01, 42.98, 28.38, 28.26, 21.68, 13.18, 10.40;HRMS (ESI-TOF) m/z Calcd for C₃₀H₄₅N₄O₅ [M+H]⁺: 541.3384, found:541.3387.

tert-Butyl(3-(1,1-dioxidothiomorpholino)-5-methylphenyl)-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(10m)

Substrate 1a was aminated following the general meta-aminationprocedure. After purification by preparative thin-layer chromatography,Compound 10m was obtained in 70% yield as a light yellow solid, ¹H NMR(400 MHz, CDCl₃) δ 8.15 (s, 1H), 6.71 (s, 1H), 6.66 (s, 1H), 6.48 (s,1H), 4.87 (s, 2H), 3.81-3.69 (m, 7H), 3.07-2.98 (m, 4H), 2.24 (s, 3H),2.23-2.19 (m, 6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 163.64,155.16, 154.51, 148.83, 147.34, 143.93, 139.30, 124.76, 123.78, 119.61,114.42, 112.37, 80.32, 59.85, 53.40, 50.33, 47.62, 28.24, 21.74, 13.21,10.42; HRMS (ESI-TOF) m/z Calcd for C₂₅H₃₆N₃O₅S [M+H]⁺: 490.2370, found:490.2368.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-thiomorpholinophenyl)carbamate (10n)

Substrate 1a was aminated following the general meta-amination procedureusing Pd(OAc)₂ (3.4 mg, 15 mol %), L24 (5.1 mg, 15 mol %), AgOAc (50.1mg, 0.3 mmol) and NBE-CO₂Me (45.7 mg, 0.3 mmol). After purification bypreparative thin-layer chromatography, Compound 10n was obtained in 62%yield as a colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 8.15 (s, 1H), 6.58(s, 2H), 6.47 (s, 1H), 4.87 (s, 2H), 3.72 (s, 3H), 3.45-3.38 (m, 4H),2.71-2.64 (m, 4H), 2.24-2.18 (m, 9H), 1.39 (s, 9H); ¹³C NMR (150 MHz,CDCl₃) δ 163.61, 155.34, 154.74, 151.33, 148.85, 143.49, 138.66, 124.60,123.78, 118.82, 115.65, 113.26, 80.10, 59.84, 53.59, 52.27, 28.30,26.79, 21.71, 13.21, 10.44; HRMS (ESI-TOF) m/z Calcd for C₂₅H₃₆N₃O₃S[M+H]⁺: 458.2472, found: 458.2469.

tert-Butyl ((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-(4-oxopiperidin-1-yl)phenyl)-carbamate (10o)

Substrate 1a was aminated following the general meta-amination procedureusing Pd(OAc)₂ (3.4 mg, 15 mol %), L24 (5.1 mg, 15 mol %), AgOAc (50.1mg, 0.3 mmol) and NBE-CO₂Me (45.7 mg, 0.3 mmol). After purification bypreparative thin-layer chromatography, Compound 10o was obtained in 53%yield as a colorless liquid, ¹H NMR (400 MHz, CDCl₃) δ 8.14 (s, 1H),6.71 (s, 1H), 6.61 (s, 1H), 6.56 (s, 1H), 4.88 (s, 2H), 3.73 (s, 3H),3.50 (t, J=6.0 Hz, 4H), 2.47 (t, J=6.0 Hz, 4H), 2.25 (s, 3H), 2.21 (s,6H), 1.39 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 208.41, 163.61, 155.33,154.69, 148.97, 148.83, 143.73, 138.94, 124.63, 123.77, 118.81, 114.26,112.10, 80.16, 59.84, 53.57, 49.00, 40.69, 28.29, 21.77, 13.20, 10.43;HRMS (ESI-TOF) m/z Calcd for C₂₆H₃₆N₃O₄ [M+H]⁺: 454.2700, found:454.2699.

Meta-Alkynylation of Anilines

General procedure for alkynylation of anilines:

Substrate 1 or 2 (0.1 mmol), alkynylating reagent (52.2 mg, 0.2 mmol),Pd(OAc)₂ (2.2 mg, 10 mol %), L25 (8.2 mg, 30 mol %), Ag₂CO₃ (41.1 mg,0.15 mmol), NBE-CO₂Me (38.0 mg, 0.25 mmol), LiF (5.2 mg, 0.2 mmol) andDCM (1.0 mL) were added to a 2-dram vial. The vial was capped and closedtightly. Then the reaction mixture was then stirred at 100° C. for 24hours. After cooling to room temperature, the mixture was passed througha pad of Celite® with DCM as the eluent to remove the insolubleprecipitate. The resulting solution was concentrated and purified bypreparative TLC to afford the desired product Compound 14.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methyl-5-((triisopropylsilyl)ethynyl)phenyl)-carbamate(14a)

Substrate 1a was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14a was obtained in 72% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.11 (s, 1H), 7.05 (s, 2H), 4.87 (s,2H), 3.72 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.40 (s, 9H), 1.10 (s,21H); ¹³C NMR (150 MHz, CDCl₃) δ 163.70, 154.94, 154.59, 148.95, 142.57,138.08, 129.93, 127.64, 127.31, 124.69, 123.75, 123.25, 107.04, 89.82,80.42, 59.83, 53.32, 28.22, 21.10, 18.63, 13.18, 11.29, 10.44; HRMS(ESI-TOF) m/z Calcd for C₃₂H₄₉N₂O₃Si [M+H]⁺: 537.3507, found: 537.3506.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(3-methoxy-5-((triisopropylsilyl)ethynyl)phenyl)-carbamate(14b)

Substrate 1b was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14b was obtained in 62% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.16 (s, 1H), 6.94 (s, 1H), 6.83 (s, 1H), 6.75 (s,1H), 4.87 (s, 2H), 3.73 (s, 3H), 3.72 (s, 3H), 2.23-2.18 (m, 6H), 1.41(s, 9H), 1.10 (s, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 163.70, 159.17,154.78, 154.49, 148.97, 143.84, 124.70, 123.95, 123.70, 122.97, 114.24,113.82, 106.82, 90.18, 80.56, 59.84, 55.39, 53.26, 28.23, 18.63, 13.18,11.27, 10.41; HRMS (ESI-TOF) m/z Calcd for C₃₂H₄₉N₂O₄Si [M+H]⁺:553.3456, found: 553.3457.

tert-Butyl(3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-((triisopropylsilyl)ethynyl)phenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)carbamate(14c)

Substrate 1x was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14c was obtained in 70% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.15 (s, 1H), 7.20 (s, 1H), 7.19-7.14 (m, 2H), 4.88(s, 2H), 4.62 (s, 2H), 3.72 (s, 3H), 2.23-2.17 (m, 6H), 1.40 (s, 9H),1.10 (s, 21H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR (150 MHz, CDCl₃) δ163.67, 154.81, 154.61, 149.02, 142.77, 141.83, 128.46, 126.71, 124.63,124.27, 123.63, 123.26, 107.06, 90.03, 80.45, 64.15, 59.82, 53.28,28.23, 25.86, 18.63, 18.31, 13.17, 11.29, 10.39, −5.35; HRMS (ESI-TOF)m/z Calcd for C₃₈H₆₃N₂O₄Si₂ [M+H]⁺: 667.4321, found: 667.4322.

tert-Butyl(3-benzyl-5-((triisopropylsilyl)ethynyl)-phenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(14d)

Substrate 1y was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14d was obtained in 50% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.28-7.22 (m, 2H), 7.18 (t, J=7.2 Hz,1H), 7.14 (s, 1H), 7.11-7.05 (m, 3H), 7.00 (s, 1H), 4.86 (s, 2H), 3.86(s, 2H), 3.69 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.36 (s, 9H), 1.09(s, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 163.72, 154.80, 154.56, 148.94,142.65, 141.02, 140.40, 129.77, 128.85, 128.39, 128.10, 127.89, 126.10,124.69, 123.86, 123.56, 106.87, 90.22, 80.49, 59.82, 53.22, 41.40,28.21, 18.64, 13.20, 11.29, 10.44; HRMS (ESI-TOF) m/z Calcd forC₃₈H₅₃N₂O₃Si [M+H]⁺: 613.3820, found: 613.3820.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(5-((triisopropylsilyl)ethynyl)-[1,1′-biphenyl]-3-yl)carbamate(14e)

Substrate 1z was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14e was obtained in 61% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.48 (d, J=7.6 Hz, 2H), 7.45-7.36 (m,4H), 7.33 (d, J=7.2 Hz, 1H), 7.31 (s, 1H), 4.94 (s, 2H), 3.71 (s, 3H),2.22 (s, 3H), 2.21 (s, 3H), 1.43 (s, 9H), 1.12 (s, 21H); ¹³C NMR (150MHz, CDCl₃) δ 163.76, 154.86, 154.55, 149.02, 143.01, 141.45, 140.14,128.90, 128.68, 127.99, 127.53, 127.10, 126.01, 124.81, 123.89, 106.78,90.51, 80.62, 59.83, 53.28, 28.29, 28.26, 18.65, 13.19, 11.30, 10.48;HRMS (ESI-TOF) m/z Calcd for C₃₇H₅₁N₂O₃S1 [M+H]⁺: 599.3663, found:599.3662.

tert-Butyl(3-fluoro-5-((triisopropylsilyl)ethynyl)-phenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(14f)

Substrate 1e was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14f was obtained in 44% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.15 (s, 1H), 7.03 (d, J=10.3 Hz, 1H),6.92 (d, J=8.1 Hz, 1H), 4.86 (s, 2H), 3.73 (s, 3H), 2.22 (s, 3H), 2.20(s, 3H), 1.40 (s, 9H), 1.10 (s, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 163.74,161.84 (d, J=245.3 Hz), 154.42, 154.21, 149.09, 144.41 (d, J=11.1 Hz),125.76, 124.84, 124.54 (d, J=10.9 Hz), 123.53, 115.79 (d, J=23.0 Hz),114.50 (d, J=23.3 Hz), 105.59 (d, J=3.3 Hz), 91.74, 80.96, 59.88, 53.09,28.18, 18.60, 13.20, 11.23, 10.38; HRMS (ESI-TOF) m/z Calcd forC₃₁H₄₆FN₂O₃Si [M+H]⁺: 541.3256, found: 541.3257.

tert-Butyl(3-chloro-5-((triisopropylsilyl)ethynyl)phenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(14g)

Substrate 1f was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14g was obtained in 59% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.28 (s, 1H), 7.27-2.24 (m, 1H), 7.20(s, 1H), 4.85 (s, 2H), 3.73 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.40(s, 9H), 1.10 (s, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 163.75, 154.40,154.18, 149.10, 144.00, 133.45, 128.83, 128.22, 127.03, 124.85, 124.70,123.53, 105.31, 92.05, 80.98, 59.89, 53.06, 28.17, 18.61, 13.20, 11.23,10.39; HRMS (ESI-TOF) m/z Calcd for C₃₁H₄₆ClN₂O₃Si [M+H]⁺: 557.2961,found: 557.2960.

tert-Butyl(3-bromo-5-((triisopropylsilyl)ethynyl)-phenyl)((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-carbamate(14h)

Substrate 1aa was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14h was obtained in 56% yield as a colorless liquid, ¹H NMR(400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.43 (s, 1H), 7.35 (s, 1H), 7.29 (s,1H), 4.85 (s, 2H), 3.73 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H), 1.40 (s,9H), 1.10 (s, 21H); ¹³C NMR (151 MHz, CDCl₃) δ 163.76, 154.38, 154.16,149.10, 144.04, 131.65, 129.88, 128.69, 125.00, 124.86, 123.55, 121.16,105.14, 92.19, 81.00, 59.89, 53.05, 28.17, 18.61, 13.20, 11.23, 10.40;HRMS (ESI-TOF) m/z Calcd for C₃₁H₄₆BrN₂O₃Si [M+H]⁺: 601.2456, found:601.2456.

tert-Butyl((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)(1-methyl-4-((triisopropylsilyl)ethynyl)-1H-indazol-6-yl)carbamate(14i)

Substrate 2j was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14i was obtained in 53% yield as a colorless solid, ¹H NMR (400MHz, CDCl₃) δ 8.15 (s, 1H), 7.96 (s, 1H), 7.35 (s, 1H), 7.17 (s, 1H),4.95 (s, 2H), 3.98 (s, 3H), 3.72 (s, 3H), 2.23 (s, ³H), 2.21 (s, 3H),1.41 (s, 9H), 1.15 (s, 21H); ¹³C NMR (150 MHz, CDCl₃) δ 163.79, 154.81,154.68, 148.93, 141.15, 139.74, 132.28, 125.06, 124.86, 123.91, 123.35,115.60, 107.69, 103.86, 94.66, 80.72, 59.84, 53.70, 35.69, 28.23, 18.66,13.18, 11.26, 10.50; HRMS (ESI-TOF) m/z Calcd for C₃₃H₄₉N₄O₃Si [M+H]⁺:577.3568, found: 577.3568.

tert-Butyl(1-acetyl-4-((triisopropylsilyl)ethynyl)-indolin-6-yl)((4-methoxy-3,5-dimethylpyridin-2-yl)-methyl)carbamate(14j)

Substrate 2g was alkynylated following the general meta-alkynylationprocedure. After purification by preparative thin-layer chromatography,Compound 14j was obtained in 46% yield as a light yellow solid,Rotameric mixture, ratio of the rotamers=84/16; ¹H NMR (400 MHz, CDCl₃)δ 8.15 (s, 1H), 8.11 (s, 0.84H), 7.19 (s, 0.16H), 6.97 (s, 1H),4.93-4.82 (m, 2H), 4.18-4.96 (m, 2H), 3.72 (s, 3H), 3.17 (t, J=8.5 Hz,1.68H), 3.05 (t, J=8.4 Hz, 0.32H), 2.33-2.14 (m, 9H), 1.40 (s, 9H), 1.10(s, 21H); ¹³C NMR (150 MHz, CDCl₃) resonances for the minor rotamer areenclosed in parenthesis ( ): ¹³C NMR (150 MHz, CDCl₃) δ 168.55 (168.27),163.74, 154.98 (154.84), 154.67, 148.88, 142.87 (142.36), 142.27(141.67), 131.84 (134.48), 125.21 (124.90), 124.68 (124.64), 123.98,119.35 (120.76), 116.60 (114.42), 104.10 (103.69), 94.27 (95.13), 80.46(80.63), 59.82, 53.49, 48.97 (48.06), 28.24, 27.72 (26.48), 24.11(24.34), 18.62, 13.17, 11.18, 10.52 (10.45); HRMS (ESI-TOF) m/z Calcdfor C₃₅H₅₂N₃O₄Si [M+H]⁺: 606.3722, found: 606.3722.

3.18 Meta-Arylation of Phenylacetic Acid

General Procedure for Arylation of Phenylacetic Acid:

2-Methyl phenylacetic acid (0.1 mmol), Ar—I (0.25 mmol), Pd(OAc)₂ (2.2mg, 10 mol %), L24 (6.8 mg, 20 mol %), Ag₂CO₃ (20.7 mg, 0.075 mmol),NBE-CO₂Me (38.0 mg, 0.25 mmol), K₂HPO₄ (35 mg, 0.2 mmol) and HFIP (1.0mL) were added to a 10 mL vial. The vial was capped and closed tightly.Then the reaction mixture was first stirred at room temperature for 5minutes and then heated to 100° C. for 24 hours. After cooling to roomtemperature, 0.05 mL HOAc was added. Then the mixture was passed througha pad of Celite® with DCM as the eluent to remove the insolubleprecipitate. The resulting solution was concentrated and purified bypreparative TLC using 2:1 hexanes:EtOAc (with 1% HOAc) as the eluent toafford the desired product Compound 15.

2-(4,4′-dimethyl-[1,1′-biphenyl]-3-yl)acetic acid

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J=8.0 Hz, 2H),7.43-7.36 (m, 2H), 7.27-7.15 (m, 3H), 3.72 (s, 2H), 2.38 (s, 3H), 2.35(s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 177.3, 139.2, 137.8, 136.9, 135.7,132.3, 130.8, 129.4, 128.9, 126.8, 126.2, 39.0, 21.1, 19.2; HRMS(ESI-TOF) m/z Calcd for C₁₆H₁₇O₂ ⁺[M+H]⁺: 241.1223, found: 241.1223.

Gram-Scale Reaction for Meta-Arylation of Anilines

Compound 1a (1.43 g, 4.0 mmol), methyl 4-iodobenzoate (2.1 g, 8.0 mmol),Pd(OAc)₂ (44.8 mg, 0.2 mmol, 5 mol %), Ligand L12 (30.4 mg, 0.2 mmol, 5mol %), AgOAc (2.0 g, 12.0 mmol), NBE-CO₂Me (608.8 mg, 4.0 mmol) and DCE(10.0 mL) were added to a 150 mL sealed tube. Then the reaction mixturewas stirred at 100° C. for 48 hours. After cooling to room temperature,the mixture was passed through a pad of Celite® with DCM as the eluentto remove the insoluble precipitate. The resulting solution wasconcentrated and purified by silica gel column chromatography to affordthe desired arylated product in 93% yield as a colorless liquid.

Directing Group Removal for Amines

General Procedure for Directing Group Removal from Amines:

To a solution of 9n (981.2 mg, 2.0 mmol) in DCM (8.0 mL) was added TFA(1.2 mL, 16.0 mmol) at room temperature. The mixture was stirring atroom temperature for another 24 hours. The resulting solution wasdiluted by DCM (50 mL), and washed by with a saturated sodium carbonatesolution. The aqueous phase was extracted with DCM (3×10 mL). Thecombined organic phases were dried by Na₂SO₄ and concentrated to afforda solid, which was used for next step without purification.

To a mixture of the solid amine obtained in the previous step (39.0 mg,0.1 mmol), was added DDQ (22.7 mg, 0.1 mmol), DCM/H₂O (0.6 mL/0.2 mL)and Boc₂O (69 μL, 0.3 mmol). The mixture was stirred at room temperaturefor another 24 hours. Next, the mixture was passed through a pad ofCelite® with DCM as the eluent to remove the insoluble precipitate. Theresulting solution was concentrated and purified by preparative TLC toafford the desired arylated product (Hexane/EA=3/1) as a colorless solid(25.2 mg, 74% yield).

Methyl3′-((tert-butoxycarbonyl)amino)-5′-methyl-[1,1′-biphenyl]-4-carboxylate(12)

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J=8.3 Hz, 2H), 7.65 (d, J=8.4 Hz,2H), 7.47 (s, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.60 (s, 1H), 3.95 (s,3H), 2.41 (s, 3H), 1.55 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 167.00,152.74, 145.45, 140.75, 139.45, 138.85, 129.96, 128.88, 127.07, 127.04,122.83, 118.79, 114.53, 80.61, 52.09, 28.33, 21.57.

Directing Group Removal for Phenols

General Procedure for Directing Group Hydrogenolysis (Phenols):

Substrate 7e (0.1 mmol) and 10% Pd/C (30.0 mg), were charged to a 10 mLvial equipped with a stir bar and a rubber septa. The vial was evacuatedand purged with nitrogen, followed by addition of 2.0 mL of MeOH. Thevial was then placed in an autoclave with a needle piercing the septa.The autoclave was purged with hydrogen three times then filled to apressure of 30 bar H₂. The autoclave was placed on a stirring plate atroom temperature overnight with good stirring. The resulting solutionwas diluted with EtOAc (5.0 mL) and passed through a plug of Celite®with EtOAc as the eluent. The filtrate was concentrated and purified bypreparative TLC to provide the desired phenol 13 in 79% yield.

Methyl4′-methyl-3′-((3-methylpyridin-2-yl)methoxy)-[1,1′-biphenyl]-2-carboxylate(13)

Colorless solid, ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J=7.7 Hz, 1H),7.53-7.44 (t, J=7.6 Hz, 1H), 7.41-7.32 (m, 2H), 7.13 (d, J=7.6 Hz, 1H),6.79 (dd, J=7.5, 1.7 Hz, 1H), 6.74 (d, J=1.7 Hz, 1H), 5.02 (s, 1H), 3.68(s, 3H), 2.28 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ 169.56, 153.56,141.87, 140.18, 131.17, 130.84, 130.69, 130.53, 129.53, 127.02, 122.91,120.66, 114.86, 52.12, 15.56; HRMS (ESI-TOF) m/z Calcd for C₁₅H₁₄O₃[M+H]⁺: 243.1016, found: 243.1017.

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Each of the patents, patent applications and articles cited herein isincorporated by reference.

The foregoing description and the examples are intended as illustrativeand are not to be taken as limiting. Still other variations within thespirit and scope of this invention are possible and will readily presentthemselves to those skilled in the art.

1. A method of forming a reaction product containing carbon-to-carbon(C—C) bond to an aryl or heteroaryl substituent at a position meta to asubstituent previously present on the ring of an aromatic reactivesubstrate compound comprising the steps of a) heating a reaction mixtureto a temperature of about 70° to about 120° C., said reaction mixturecontaining i) said aromatic reactive substrate compound of Formula Idissolved or dispersed in a non-aqueous solvent having a boiling pointat 1 atmosphere of about 40° to about 200° C., that further containsdissolved or dispersed therein ii) a catalytic amount of a Pd(II)catalyst, iii) a ligand of Formula III is present at about 10 to about50 mole percent based on the moles of reactive substrate, iv) anethylenically unsaturated bicyclic compound of Formula II as a transientmediator present in excess over the amount of reactive substrate, v)about 1.5 to about 5 equivalents of an oxidant based on the amount ofsaid reactive substrate, and vi) about 1.1 to about 10 equivalents of aiodo-substituted aryl or heteroaryl coupling agent (Ar—I); and b)maintaining said temperature for a time period sufficient to carry outthe C—C bond formation at a position meta to said substituent and form areaction product whose structural formula is shown in Formula IA

wherein said iodo-substituted aryl or heteroaryl coupling agent beingadditionally unsubstituted, or said iodo-substituted aryl coupling agentbeing further substituted at the meta and para positions with one or twosubstituents independently selected from the group consisting of halogen(fluoro, chloro, bromo or iodo), C₁-C₇-hydrocarbyl that is straight,branched or cyclic, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—),C₁-C₇-hydrocarbylthioxy (C₁-C₇—S—), cyano, nitro,perfluoro-C₁-C₃-hydrocarbyl, carboxy C₁-C₇-hydrocarbyl,C₁-C₇-hydrocarboyl (acyl), protected hydroxyl, protectedhydroxyl-substituted C₁-C₇-hydrocarbyl that is straight, branched orcyclic, di-(C₁-C₇-hydrocarbyl) C₁-C₇-hydrocarbylphosphonate, protectedamino wherein the protecting group(s) contains up to 10 carbon atoms andthe amine nitrogen has no reactive hydrogen, and a fused ring thatincludes 3 or 4 added ring atoms, and at the ortho position by a carboxyC₁-C₇-hydrocarbyl or NH—C₁-C₇-hydrocarboyl group; or saidiodo-substituted heteroaryl coupling agent being further substitutedwith one or two substituents independently selected from the groupconsisting of halogen other than iodo, C₁-C₇-hydrocarbyl that isstraight, branched or cyclic, C₁-C₇-hydrocarbyloxy (C₁-C₇—O—),C₁-C₇-hydrocarbylthioxy (C₁-C₇—S—), perfluoro-C₁-C₃-hydrocarbyl, carboxyC₁-C₇-hydrocarbyl, C₁-C₇-hydrocarboyl (acyl), a fused ring that includes3 or 4 added ring atoms and in which any nitrogen atom present is freeof reactive hydrogens; said aromatic reactive substrate compound has astructural formula shown in Formula I, below:

wherein, Ring A is a heteroaromatic or carbocyclic aromatic ringstructure in which the bond shown to X is at the 1-position of the ringand the substituent bonded at the 1-position constitutes the substituentpreviously present on the ring, the ring position rotated clock-wisefrom the 1-position is the ortho-position at which a hydrogen (H) isbonded, and the next position clock-wise from the ortho-position atwhich another hydrogen (H) is bonded is the meta-position and is theposition at which the new C—C bond is formed, said Ring A containing asingle ring or two fused rings having a total of 5 to 10 ring atoms andin which the ring bonded to X is aromatic and any other ring fused tothat aromatic ring is independently aromatic or aliphatic, and in whicha heteroaromatic ring structure contains one, two or three heteroatomsthat can independently be nitrogen, oxygen or sulfur atoms, said Ring Aoptionally further containing 1, 2 or 3 substituents other than hydrido(H) bonded to the ring atoms, which substituents are selected from thegroup consisting of halo other than iodo (fluoro, chloro or bromo),C₁-C₇-hydrocarbyl that is straight, branched or includes a 4- to6-membered ring bonded to a straight or branched chain,C₁-C₇-hydrocarbyloxy (C₁-C₇—O—), C₁-C₇-hydrocarbylthioxy (C₁-C₇—S—),C₁-C₂-hydrocarbyldioxy, cyano, nitro, perfluoro-C₁-C₃-hydrocarbyl,carboxy C₁-C₇-hydrocarbyl, C₁-C₇-hydrocarboyl (acyl), protected aminowherein the protecting group(s) contains up to 10 carbon atoms, and afused ring; n is zero (0) or one, such that the methylene group Y withinthe brackets is absent when n is zero, and present when n is one, X is O(oxygen) or NPG (a nitrogen bonded to a protecting group) when n is 1,and NPG or CH₂ (methylene) when n is zero, Ring B is a heteroaromaticsingle 6-membered ring or a fused 6,6- or 5,6-membered ring systemcontaining the depicted nitrogen atom and 1 or 2 other nitrogen ringatoms, Z is carbon when n is zero or 1, and Z is nitrogen (a) when n iszero, and (b) the double bond depicted is absent and replaced by adouble bond at the position of the dashed line, said Ring B optionallyfurther containing 1, 2 or 3 substituents other than hydrido (H) bondedto the ring atoms, which substituents are selected from the groupconsisting of C₁-C₇-hydrocarbyl that is straight, branched or includes a4- to 6-membered ring bonded to a straight or branched chainC₁-C₃-substituent, C₁-C₇-hydrocarbyloxy,trifluoromethyl-C₁-C₃-hydrocarbyl, trifluoromethyl-C₁-C₃-hydrocarbyloxy,and a fused ring; said transient mediator is an ethylenicallyunsaturated bicyclic compound of Formula II

wherein A is CH₂, C═O or O, each of R⁵, R⁶, R⁷, R⁸, R⁹, and R¹⁰ isindependently H, C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyloxy,C₁-C₆-hydrocarbyl carboxylate, C₁-C₆-hydrocarboyl, one or both of R⁵plus R⁶ and R⁷ plus R⁸ together with the carbon atom to which they arebonded form one or two carbonyl groups, or one each of R⁵ and R⁶, or R⁷and R⁸ together with the atoms to which they are bonded form a further4- to 6-membered aliphatic or aromatic ring that itself can beindependently substituted with one or two substituent groups selectedfrom the group consisting of a C₁-C₆-hydrocarbyl, aC₁-C₆-hydrocarbyloxy, a C₁-C₆-hydrocarbyl carboxylate and a nitro group;and said ligand having the structure of Formula III

wherein R¹⁵ is an acyl group containing 2 to about 12 carbon atoms or aperfluorinated acyl group containing 2 to about 6 carbon atoms, R¹⁶ ishydrido or C₁-C₆-hydrocarbyl, R¹⁷ is hydrido, C₁-C₆-hydrocarbyl ortrifluoromethyl, R¹⁸ is hydrido or C₁-C₆-hydrocarbyl, or R¹⁶ and R¹⁷ orR¹⁷ and R¹⁸ together with the carbon atoms to which they are bonded forma 6-membered ring with the depicted pyridine ring, m and p are the sameand are zero or 1, such that when m and p are zero, the bracketed carbonatoms are absent and the NHR¹⁵ group is bonded directly to the depictedpyridine ring, and when m and p are both one, R¹⁹ and R²⁰ together withthe carbons to which they are bonded form a phenyl ring.
 2. The methodaccording to claim 1, wherein n is
 1. 3. The method according to claim2, wherein Ring B is a heteroaromatic single 6-membered ring and Z is acarbon atom.
 4. The method according to claim 3, wherein Ring B has thestructural formula shown below, wherein the dotted line

denotes a bond to methylene group Y, and R¹, R² and R³ are independentlyhydrido, C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyloxy ortrifluoromethyl-C₁-C₃-hydrocarbyloxy, but at least one is other thanhydrido.
 5. The method according to claim 4, wherein Ring A is a singlering structure.
 6. The method according to claim 5, wherein said singlering structure is a heteroaromatic ring.
 7. The method according toclaim 7, wherein said single heteroaromatic ring contains a ring heteroatom or a ring substituent in the meta-position rotated counterclock-wise from said 1-position.
 8. The method according to claim 4,wherein Ring A is a fused ring structure containing two rings.
 9. Themethod according to claim 5, wherein said single ring structure is acarbocyclic aromatic ring.
 10. The method according to claim 9, whereinsaid carbocyclic aromatic ring contains at least one substituent group.11. The method according to claim 1, wherein R¹⁵ is acetyl or1-adamantoyl.
 12. The method according to claim 11, wherein R¹⁶ ishydrido, R¹⁷ is C₁-C₆-hydrocarbyl or trifluoromethyl and R¹⁸ is hydrido.13. The method according to claim 1, wherein A is CH₂ and R¹⁰ isC₁-C₆-hydrocarbyl carboxylate in a transient mediator compound ofFormula II.
 14. The method according to claim 13, wherein the remainingsubstituent R groups of a transient mediator compound of Formula II arehydrido.
 15. The method according to claim 1 including the further stepof recovering said reaction product of Formula IA.
 16. The methodaccording to claim 2 including the further step of reductively cleavingsaid reaction product of Formula IA to form products Ring A-Prod andRing B-Prod whose structural formulas are shown below


17. The method according to claim 4, wherein X is O.
 18. The methodaccording to claim 4, wherein X is NPG.
 19. The method according toclaim 1, wherein n is zero.
 20. A substituted 3-amino-2-hydroxypyridineligand having the structure of of Formula III

wherein R¹⁵ is an acyl group containing 2 to about 12 carbon atoms or aperfluorinated acyl group containing 2 to about 6 carbon atoms, R¹⁶ ishydrido or C₁-C₆-hydrocarbyl, R¹⁷ is hydrido, C₁-C₆-hydrocarbyl ortrifluoromethyl, R¹⁸ is hydrido or C₁-C₆-hydrocarbyl, or R¹⁶ and R¹⁷ orR¹⁷ and R¹⁸ together with the carbon atoms to which they are bonded forma 6-membered ring with the depicted pyridine ring, m and p are the sameand are zero or 1 such that m and p are zero, the bracketed carbon atomsare absent and the NHR¹⁵ group is bonded directly to the depictedpyridine ring, and when m and p are both one, R¹⁹ and R²⁰ together withthe carbons to which they are bonded form a phenyl ring.
 21. Thesubstituted 3-amino-2-hydroxypyridine ligand according to claim 20,wherein m and p are both zero, and at least one of R¹⁶, R¹⁷ and R¹⁸ isother than hydrido.
 22. The substituted 3-amino-2-hydroxypyridine ligandaccording to claim 21, wherein R¹⁵ is acetyl, 1-adamantoyl ortrifluoroacetyl and R¹⁶ and R¹⁸ are hydrido.
 23. The substituted3-amino-2-hydroxypyridine ligand according to claim 21, wherein one ofR¹⁶ and R¹⁷ is C₁-C₆-hydrocarbyl, the other is hydrido, R¹⁸ is hydridoand R¹⁵ is acetyl.
 24. The substituted 3-amino-2-hydroxypyridine ligandaccording to claim 21, selected from the group consisting of one or moreof the ligands having a structural formula shown below


25. The substituted 3-amino-2-hydroxypyridine ligand according to claim20, wherein R¹⁶ and R¹⁷, or R¹⁷ and R¹⁸ together with their bondedcarbons form a 6-membered aromatic ring so that the ligand is aderivative of a quinoline or isoquinoline of Formulas IIIb and IIIc,respectively,


26. The substituted 3-amino-2-hydroxypyridine ligand according to claim25, whose structural formula is shown below


27. The substituted 3-amino-2-hydroxypyridine ligand according to claim20, wherein m and p are both one and R¹⁹ and R²⁰ together with thecarbons to which they are bonded form a phenyl ring whose structure isshown in Formula IIId, below